Methods for identifying compounds for regulating muscle mass of function using amylin receptors

ABSTRACT

Screening methods for identifying compounds that bind to or activate amylin receptors (AR) and regulate or potentially regulate skeletal muscle mass or function in vivo. Also disclosed are screening methods for identifying compounds that prolong or augment the activation of ARs or of AR signal transduction pathways, increase AR or increase amylin expression are provided. Pharmaceutical compositions comprising AR agonists, antibodies to AR and methods for increasing skeletal muscle mass or function or for the treatment of skeletal muscle atrophy using AR as the target for intervention and methods for treatment of muscular dystrophies are described.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/392,317, filed Jun. 27, 2002, which is hereinincorporated by reference in its entirety.

TECHNICAL FIELD

[0002] The present invention relates to methods of identifying candidatecompounds for regulating skeletal muscle mass or function or regulatingthe activity or expression of amylin receptors. The invention alsorelates to methods for the treatment of skeletal muscle atrophy ormethods for inducing skeletal muscle hypertrophy using amylin receptorsas the target for intervention and to methods of treating musculardystrophies using amylin receptors as targets.

BACKGROUND

[0003] Amylin Receptors and Ligands

[0004] Amylin, a 37 amino acid peptide, and as functionally andstructurally related analogs has several physiological functionsincluding cardiovascular, immunological, renal, neuronal and metaboliceffects. Included in these physiological functions are vasodilation,glycogenolysis, modulation of glandular secretion, modulation of foodintake, modulation of stomach emptying and modulation of cardiac output.

[0005] Amylin is the ligand/agonist of the amylin receptors. Amylinbinds to and activates the amylin receptors.

[0006] There are two amylin receptors (AR) resulting from interaction ofthe same receptor membrane proteins, the calcitonin receptor and itssplice variants, with two receptor activity modifying proteins, RAMP1and RAMP3, identified to date which belong to G-protein coupled receptor(GPCR) class. Agonist activation of amylin receptors leads to G_(αs)activation of adenylate cyclase. Adenylate cyclase catalyzes theformation of cAMP, which in turn has multiple effects including theactivation of protein kinase A, intracellular calcium release andactivation of mitogen-activated protein kinase (MAP kinase).

[0007] Amylin receptors have been cloned from human, guinea pig, rabbit,pig, rat, and mouse. ARs each have unique distribution patterns. Inhumans three isoforms of the AR receptor have been cloned. Homologs forthese three isoforms have been identified in other species.

[0008] The Amylin receptors can be pharmacologically distinguished fromnon-amylin receptors, through the use of receptor selective agonists andantagonists. These selective agonists and antagonist have been useful inevaluating the role of the amylin receptors in amylin mediatedbiological responses.

[0009] Skeletal Muscle Atrophy and Hypertrophy

[0010] Skeletal muscle is a plastic tissue that readily adapts tochanges in physiological demand for work and metabolic need. Hypertrophyrefers to an increase in skeletal muscle mass while skeletal muscleatrophy refers to a decrease in skeletal muscle mass. Acute skeletalmuscle atrophy is traceable to a variety of causes including, but notlimited to: disuse due to surgery, bed rest, or broken bones;denervation/nerve damage due to spinal cord injury, autoimmune disease,or infectious disease; glucocorticoid use for unrelated conditions;sepsis due to infection or other causes; nutrient limitation due toillness or starvation; and space travel. Skeletal muscle atrophy occursthrough normal biological processes, however, in certain medicalsituations this normal biological process results in a debilitatinglevel of muscle atrophy. For example, acute skeletal muscle atrophypresents a significant limitation in the rehabilitation of patients fromimmobilizations, including, but not limited to, those accompanying anorthopedic procedure. In such cases, the rehabilitation period requiredto reverse the skeletal muscle atrophy is often far longer than theperiod of time required to repair the original injury. Such acute disuseatrophy is a particular problem in the elderly, who may already sufferfrom substantial age-related deficits in muscle function and mass,because such atrophy can lead to permanent disability and prematuremortality.

[0011] Skeletal muscle atrophy can also result from chronic conditionssuch as cancer cachexia, chronic inflammation, AIDS cachexia, chronicobstructive pulmonary disease (COPD), congestive heart failure, geneticdisorders, e.g., muscular dystrophies, neurodegenerative diseases andsarcopenia (age associated muscle loss). In these chronic conditions,skeletal muscle atrophy can lead to premature loss of mobility, therebyadding to the disease-related morbidity.

[0012] Little is known regarding the molecular processes which controlatrophy or hypertrophy of skeletal muscle. While the initiating triggerof the skeletal muscle atrophy is different for the various atrophyinitiating events, several common biochemical changes occur in theaffected skeletal muscle fiber, including a decrease in proteinsynthesis and an increase in protein degradation and changes in bothcontractile and metabolic enzyme protein isozymes characteristic of aslow (highly oxidative metabolism/slow contractile protein isoforms) tofast (highly glycolytic metabolism/fast contractile protein isoforms)fiber switch. Additional changes in skeletal muscle that occur includethe loss of vasculature and remodeling of the extracellular matrix. Bothfast and slow twitch muscle demonstrate atrophy under the appropriateconditions, with the relative muscle loss depending on the specificatrophy stimuli or condition. Importantly, all these changes arecoordinately regulated and are switched on or off depending on changesin physiological and metabolic need.

[0013] The processes by which atrophy and hypertrophy occur areconserved across mammalian species. Multiple studies have demonstratedthat the same basic molecular, cellular, and physiological processesoccur during atrophy in both rodents and humans. Thus, rodent models ofskeletal muscle atrophy have been successfully utilized to understandand predict human atrophy responses. For example, atrophy induced by avariety of means in both rodents and humans results in similar changesin muscle anatomy, cross-sectional area, function, fiber type switching,contractile protein expression, and histology. In addition, severalagents have been demonstrated to regulate skeletal muscle atrophy inboth rodents and in humans. These agents include anabolic steroids,growth hormone, insulin-like growth factor I, and beta-adrenergicagonists. Together, these data demonstrate that skeletal muscle atrophyresults from common mechanisms in both rodents and humans.

[0014] Muscular dystrophies encompass a group of inherited, progressivemuscle disorders, distinguished clinically by the selective distributionof skeletal muscle weakness. Treatment of muscular dystrophies withcorticosteroids slows immune-mediated muscle fiber damage but alsocauses muscle atrophy.

[0015] While some agents have been shown to regulate skeletal muscleatrophy and are approved for use in humans for this indication, theseagents have undesirable side effects such as hypertrophy of cardiacmuscle, neoplasia, hirsutism, androgenization of females, increasedmorbidity and mortality, liver damage, hypoglycemia, musculoskeletalpain, increased tissue turgor, tachycardia, and edema. Currently, thereare no highly effective and selective treatments for either acute orchronic skeletal muscle atrophy. Thus, there is a need to identify othertherapeutic agents that regulate skeletal muscle atrophy.

SUMMARY OF THE INVENTION

[0016] The present invention relates to the use of amylin receptors toidentify candidate compounds that are potentially useful in thetreatment of skeletal muscle atrophy and or to induce skeletal musclehypertrophy. In particular, the invention provides in vitro methods foridentifying candidate compounds for regulating skeletal muscle mass orfunction comprising contacting a test compound with a cell expressingamylin receptors, or contacting a test compound with isolated amylinreceptors protein, and determining whether the test compound eitherbinds to or activates amylin receptors. Another embodiment of theinvention relates to a method for identifying candidate therapeuticcompounds from a group of one or more candidate compounds which havebeen determined to bind to or activate amylin receptors comprisingadministering the candidate compound to a non-human animal anddetermining whether the candidate compound regulates skeletal musclemass or muscle function in the treated animal.

[0017] A further embodiment of the invention relates to a method foridentifying candidate compounds that selectively activate amylinreceptor for regulating skeletal muscle mass or function comprising: (i)contacting a test compound with a cell expressing a functional amylinreceptor, and determining a level of activation of amylin receptorresulting from the test compound; (ii) contacting a test compound with acell expressing a functional calcitonin receptor, and determining thelevel of activation of calcitonin receptor resulting from the testcompound and evaluation of the candidate compounds for regulatingskeletal muscle mass or function.

[0018] The invention further provides methods for identifying candidatecompounds that prolong or augment the agonist-induced activation ofamylin receptors or of amylin receptor signal transduction pathwaycomprising: (i) contacting a test compound; with a cell which expressesa functional amylin receptor (ii) treating the cell with an amylinreceptor agonist for a sufficient time and at a sufficient concentrationto cause desensitization of the amylin receptor in control cells;followed by (iii) determining the level of activation of amylinreceptors and identifying test compounds that prolong or augment theactivation of an amylin receptor or an amylin receptor signaltransduction pathway as candidate compounds for regulating skeletalmuscle mass or function.

[0019] The invention further provides methods for identifying candidatecompounds that increase amylin, or amylin receptor expression comprisingcontacting a test compound with a cell or cell lysate containing areporter gene operatively associated with an amylin or amylin receptorgene regulatory element and detecting expression of the reporter gene.Test compounds that increase expression of the reporter gene areidentified as candidate compounds for increasing expression.

[0020] The present invention also relates to the use of amylin receptoragonists, expression vectors encoding a functional amylin receptor,expression vectors encoding a constitutively active amylin receptor orcompounds that increase expression of amylin receptors, or amylin toincrease skeletal muscle mass or function or to treat skeletal muscleatrophy. In particular, the invention provides methods of treatingskeletal muscle atrophy, in a subject in need of such treatment,comprising administering to the subject a safe and effective amount ofan amylin receptor agonist, an expression vector encoding a functionalamylin receptor, an expression vector encoding a constitutively activeamylin receptor, an expression vector encoding amylin or an amylinanalog, or a compound that increases expression of amylin receptor, oramylin. In a particular embodiment, the present invention relates to amethod for treating skeletal muscle atrophy in a subject in need of suchtreatment comprising administering to the subject a safe and effectiveamount of an amylin receptor agonist in conjunction with a safe andeffective amount of a compound that prolongs or augments theagonist-induced activation of amylin receptors, or of an amylin receptorsignal transduction pathway.

[0021] The invention further provides for pharmaceutical compositionscomprising a safe and effective amount of an amylin receptor agonist anda pharmaceutically acceptable carrier. In a particular embodiment thepharmaceutical composition comprises a chimeric or human antibodyspecific for an amylin receptor. In another particular embodiment thepharmaceutical composition comprises amylin or an amylin analog.

[0022] The present invention also provides for antibodies to amylinreceptors and in particular to chimeric or human antibodies that areagonists of amylin receptors.

SEQUENCE LISTING DESCRIPTION

[0023] Each of the amylin receptor nucleotide and protein sequences oramylin analog protein sequence included in the sequence listing, alongwith the corresponding Genbank or Derwent accession number(s) and animalspecies from which it is cloned, is shown in Table I. Also shown areaccession numbers for related nucleotide sequences that encodeidentical, or nearly identical, amino acid sequences as the sequenceshown in the sequence listing. These related sequences differ mainly inthe amount of 5′ or 3′ untranslated sequence shown. TABLE I SEQ IDGenbank (GB) or Related Genbank NO: Derwent (D) (GB) or Derwentnucleotide, Accession No. for (D) Accession Sequence Description aminoacid Species nucleotide sequence Nos. Calcitonin Receptors: calcitoninreceptor 1, 2 human U26553 (GB) AB022177 (GB) C1a AB022178 (GB)calcitonin receptor 3, 4 human X69920 (GB) AAQ58997 (D) C1a I72177 (GB)I68246 (GB) I67990 (GB) I40808 (GB) AAR51702 (D) AAQ62283 (D) I72200(GB) I68269 (GB) I68013 (GB) I40831 (GB) AAR51704 (D) AAQ42411 (D)AAR37424 (D) calcitonin receptor 5, 6 human X82466 (GB) AC003078 (GB)C1a calcitonin receptor 7, 8 human U26554 (GB) C1a calcitonin receptor9, 10 human L00587 (GB) C1b calcitonin receptor 11, 12 human I20773 (GB)C1b calcitonin receptor 13, 14 human AAQ62282 (D) I72199 (GB) C1b I68268(GB) I68012 (GB) I40830 (GB) AAB71868 (D) calcitonin receptor 15, 16human U14637 (GB) C1b calcitonin receptor 17, 18 guinea pig U92463 (GB)calcitonin receptor 19, 20 rabbit U66365 (GB) calcitonin receptor 21, 22rabbit U73126 (GB) isoform calcitonin receptor 23, 24 pig M74420 (GB)Z31356 (GB) calcitonin receptor 25, 26 rat L13041 (GB) C1a calcitoninreceptor 27, 28 rat L14617 (GB) AAR62448 (D) C1a calcitonin receptor 29,30 rat L13040 (GB) C1b calcitonin receptor 31, 32 rat L14618 (GB)AAR62447 (D) C1b calcitonin receptor 33, 34 rat X70669 (GB) C1b partialCDS calcitonin receptor 35, 36 mouse AF056329 (GB) C1a partial CDScalcitonin receptor 37, 38 mouse AF333473 (GB) C1a-1 AF333474 (GB)AF333475 (GB) AF333476 (GB) AF333477 (GB) AF333478 (GB) AF333479 (GB)AF333481 (GB) AF333482 (GB) AF333483 (GB) AF333484 (GB) AF333485 (GB)calcitonin receptor 39, 40 mouse AF333474 (GB) C1a-2 AF333475 (GB)AF333476 (GB) AF333477 (GB) AF333478 (GB) AF333479 (GB) AF333481 (GB)AF333482 (GB) AF333483 (GB) AF333484 (GB) AF333485 (GB) calcitoninreceptor 41, 42 mouse U18542 (GB) AF333473 (GB) C1b-1 AF333474 (GB)AF333475 (GB) AF333476 (GB) AF333477 (GB) AF333478 (GB) AF333479 (GB)AF333480 (GB) AF333481 (GB) AF333482 (GB) AF333483 (GB) AF333484 (GB)AF333485 (GB) calcitonin receptor 43, 44 mouse AF333474 (GB) C1b-2AF333475 (GB) AF333476 (GB) AF333477 (GB) AF333478 (GB) AF333479 (GB)AF333480 (GB) AF333481 (GB) AF333482 (GB) AF333483 (GB) AF333484 (GB)AF333485 (GB) RAMP 1 Sequences: RAMP 1 45, 46 human AJ001014 (GB)ABA09253 (D) AC016776 (GB) AC012076 (GB) RAMP 1 47, 48 human BC000548(GB) RAMP 1 49, 50 rat AF181550 (GB) AB042887 (GB) RAMP 1 51, 52 ratAB030942 (GB) RAMP 1 53, 54 mouse AJ314840 (GB) RAMP 1 55, 56 mouseAJ250489 (GB) AF209904 (GB) AF146522 (GB) RAMP 1 57, 58 mouse BC012644(GB) AB019046 (GB) RAMP 1 partial CDS 59, 60 pig AF312385 (GB) RAMP 3Sequences: RAMP 3 61, 62 human AJ001016 (GB) AAZ98148 (D) AAA80608 (D)AAD08854 (D) AAY87263 (D) AAB25578 (D) RAMP 3 63, 64 mouse AF209907 (GB)AF146524 (GB) AJ250491 (GB) RAMP 3 65, 66 rat AB030944 (GB) AB028935(GB) RAMP 3 67, 68 rat AB042889 (GB) RAMP 3 69, 70 rat AF181552 (GB)

BRIEF DESCRIPTION OF THE FIGURES

[0024]FIG. 1 demonstrates the anti-atrophy effect of the AR agonist,amylin (administered subcutaneously, 2× daily), on the medialgastrocnemius muscle in the mouse sciatic nerve denervation atrophymodel.

[0025]FIGS. 2A and 2B demonstrate the anti-atrophy effect of amylin(administered subcutaneously, 2× daily) on glucocorticoid-inducedatrophy of the tibialis anterior muscle (FIG. 2A) and the medialgastrocnemius muscle (FIG. 2B).

[0026]FIGS. 3A and 3B demonstrate the anti-atrophy effect of amylin(administered subcutaneously, 2× daily) on the casting-induced atrophyof the tibialis anterior muscle and hypertrophy-inducing effect on thenon-casted (normal) tibialis anterior muscle (FIG. 3A) and on thecasting-induced atrophy of the medial gastrocnemius muscle and thehypertrophy inducing effect of amylin on the non-casted (normal) medialgastrocnemius muscle (FIG. 3B).

DETAILED DESCRIPTION OF THE INVENTION

[0027] Terms and Definitions:

[0028] The following is a list of definitions for terms used herein.

[0029] “Agonist” means any compound that activates a receptor. Forexample, amylin receptor agonists include, but are not limited to,amylin and amylin analogs.

[0030] “Allelic variant” means a variant form of a given gene or geneproduct. One of skill in the art recognizes that a large number of genesare present in two or more allelic forms in a population and some geneshave numerous alleles.

[0031] “Antibody” means immunoglobulin molecules or immunologicallyactive portions them, i.e., molecules that contain an antigen bindingsite which specifically binds an antigen.

[0032] “Binding affinity” means the propensity for a ligand to interactwith a receptor and is inversely related to the dissociation constantfor a specific amylin ligand-amylin receptor interaction. Thedissociation constant can be measured directly via standard saturation,competition, or kinetics binding techniques or indirectly viapharmacological techniques involving functional assays and endpoints.

[0033] “Chimeric antibody” means an antibody that contains structuralelements from two or more types antibody molecules. Chimeric antibodiesinclude, but are not limited to, antibodies known as “humanizedantibodies”.

[0034] “Amylin analogs” means substances which act as ligands of amylinreceptors. Suitable amylin analogs can be obtained from a variety ofvertebrate species and include, but are not limited to, substances suchas calcitonin gene related peptide, human calcitonin), adrenomedullin,salmon calcitonin and the amylin analogs. Preferred amylin analogs arecalcitonin gene related peptide, salmon calcitonin, human calcitonin,and adrenomedullin.

[0035] “Amylin receptor agonist” means a compound or molecule that hasthe ability to activate any amylin receptor including amylin receptor 1(calcitonin receptor+RAMP1) or amylin receptor 2 (calcitoninreceptor+RAMP3), or both. Activation of amylin receptors can be measuredas described hereinafter.

[0036] “Amylin receptor” (AR) means amylin receptor 1 (AR 1) or amylinreceptor 2 (AR2).

[0037] “AR1” means any isoforms of amylin receptor 1 (calcitoninreceptor+RAMP1) from any animal species.

[0038] The definition of AR1 includes, but is not limited to, thosereceptors for which the cDNA or genomic sequence encoding the receptorhas been deposited in a sequence database. The nucleotide and proteinsequences of these receptors are available from GenBank or Derwent andfor convenience representative sequences are given in the sequencelisting herein. (Accession No. AJ001014).

[0039] “AR2” means any isoform of amylin receptor 2 (calcitoninreceptor+RAMP3) from any animal species.

[0040] The definition of AR2 receptor includes, but is not limited to,those receptors for which the DNA sequence encoding the receptor hasbeen deposited in a sequence database. The nucleotide and proteinsequences of these receptors are available from GenBank or Derwent andfor convenience, representative sequences are given in the sequencelisting herein. (Accession No. AJ001016).

[0041] The term “Amylin Receptor or AR” also includes truncated and/ormutated proteins wherein regions of the receptor molecule not requiredfor ligand binding or signaling have been deleted or modified. Forexample one of skill in the art will recognize that a AR with one ormore conservative changes in the primary amino acid sequence would beuseful in the present invention. It is known in the art thatsubstitution of certain amino acids with different amino acids withsimilar structure or properties (conservative substitutions) can resultin a silent change, i.e., a change that does not significantly alterfunction. Conservative substitutes are well known in the art. Forexample, it is known that GPCRs can tolerate substitutions of amino acidresidues in the transmembrane alpha-helices, which are oriented towardlipid, with other hydrophobic amino acids, and remain functional. AR1sdiffering from a naturally occurring sequence by truncations and/ormutations such as conservative amino acid substitutions are alsoincluded in the definition of AR1. AR2s differing from a naturallyoccurring sequence by truncations and/or mutations such as conservativeamino acid substitutions are also included in the definition of AR2.

[0042] One of skill in the art would also recognize that ARs from aspecies other than those listed above, particularly mammalian species,would be useful in the present invention. One of skill in the art wouldfurther recognize that by using probes from the known AR species'sequences, cDNA or genomic sequences homologous to the known sequencecould be obtained from the same or alternate species by known cloningmethods. Such AR1s are also included in the definition of AR1 and suchAR2s are also included in the definition of AR.

[0043] In addition, one of skill in the art would recognize thatfunctional allelic variants or functional splice variants of ARs mightbe present in a particular species and that these variants would haveutility in the present invention. Splice variants of ARs are known, forexample U.S. Pat. Nos. 5,683,884, 5,674,981, 5,674,689, 5,622,839, and5,516,651, each of which is incorporated herein by reference. Such AR1variants are also included in the definition of AR1 and such AR2variants are also included in the definition of AR2.

[0044] Fusions of an AR polypeptide, or an AR polypeptide fragment to anon-AR polypeptide are referred to as AR fusion proteins. Using knownmethods, one of skill in the art would be able to make fusion proteinsof an AR that, while different from native AR, would remain useful inthe present invention. For example the non-AR polypeptide may be asignal (or leader) polypeptide sequence that co-translationally orpost-translationally directs transfer of the protein from its site ofsynthesis to another site (e.g., the yeast α-factor leader). Or thenon-AR polypeptide may be added to facilitate purification oridentification of the AR (e.g., poly-His, or Flag peptide). AR1 fusionproteins are also included within the definition of AR fusion proteins;AR2 fusion proteins are also included within the definition of AR.

[0045] “Inhibit” means to partially or completely block a particularprocess or activity. For example, a compound inhibits skeletal muscleatrophy if it either completely or partially prevents muscle atrophy.

[0046] As used herein, two DNA sequences are said to be “operablyassociated” if the nature of the linkage between the two DNA sequencesdoes not (1) result in the introduction of a frame-shift mutation, (2)interfere with the ability of a promoter region to direct thetranscription of the coding sequences, or (3) interfere with the abilityof the corresponding RNA transcript to be translated into a protein. Forexample, a coding sequence and regulatory sequences are operablyassociated when they are covalently linked in such a way as to place thetranscription of the coding sequence under the influence or control ofthe regulatory sequences. Thus, a promoter region is operably associatedwith a coding sequence when the promoter region is capable of effectingtranscription of that DNA sequence such that the resulting transcript iscapable of being translated into the desired protein or polypeptide.

[0047] “Percent identity” means the percentage of nucleotides or aminoacids that two sequences have in common, calculated as follows. Tocalculate the percent identity for a specific sequence (the query), therelevant part of the query sequence is compared to a reference sequenceusing the BestFit comparison computer program, Wisconsin Package,Version 10.1, available from the Genetics Computer Group, Inc. Thisprogram uses the algorithm of Smith and Waterman, Advances in AppliedMathematics, Issue 2: 482-489 (1981). Percent identity is calculatedwith the following default parameters for the BestFit program: thescoring matrix is blosum62.cmp, the gap creation penalty is 8 and thegap extension penalty is 2. When comparing a sequence to the referencesequence, the relevant part of the query sequence is that which isderived from an AR sequence. For example, where the query is anAR/purification tag fusion protein, only the AR polypeptide portion ofthe sequence is aligned to calculate the percent identity score.

[0048] “Prophylactic treatment” means preventive treatment of a subject,not currently exhibiting signs of skeletal muscle atrophy or wasting, inorder to completely or partially block the occurrence of skeletal muscleatrophy. One of skill in the art would recognize that certainindividuals are at risk for skeletal muscle atrophy as discussed in thebackground section herein. Furthermore, one of skill in the art wouldrecognize that if the biochemical changes leading to skeletal muscleatrophy are appropriately regulated, that the occurrence of atrophywould be prevented or reduced in at-risk individuals. For example,muscular dystrophy patients beginning treatment with corticosteroids areat risk for developing skeletal muscle atrophy indicating thatprophylactic treatment of such patients would be appropriate.

[0049] “Regulatory element” means a DNA sequence that is capable ofcontrolling the level of transcription from an operably associated DNAsequence. Included within this definition of regulatory element arepromoters and enhancers. E.g., an AR gene regulatory element is a DNAsequence capable of controlling the level of transcription from the ARgene.

[0050] “Reporter gene” means a coding sequence whose product can bedetected, preferably quantitatively, wherein the reporter gene isoperably associated with a heterologous promoter or enhancer elementthat is responsive to a signal that is to be measured. The promoter orenhancer element in this context is referred to herein as a “responsiveelement”.

[0051] “Selective agonist” means that the agonist has significantlygreater activity toward a certain receptor(s) compared with otherreceptors, not that it is completely inactive with regard to otherreceptors. A selective agonist for a specific receptor may show 10-fold,preferably 100-fold, more preferably 1000-fold and most preferablygreater than 1000-fold selectivity toward that receptor than otherrelated or unrelated receptors.

[0052] “Splice variant” means an mRNA or protein which results fromalternative exon usage. One of skill in the art recognizes that,depending on cell type, or even within a single cell type, a mRNA may beexpressed in a different form, as a splice variant, and thus thetranslated protein will be different depending upon the mRNA that isexpressed.

[0053] A “therapeutically effective amount” of a substance is an amountcapable of producing a medically desirable result in a treated patient,e.g., decreases skeletal muscle atrophy, increases skeletal muscle massor increases skeletal muscle function, with an acceptable benefit: riskratio; in a human or non-human mammal.

[0054] “Therapeutic treatment” means treatment of a subject in which anincrease in muscle mass or muscle function is desirable. For example,treatment of a subject currently exhibiting signs of skeletal muscleatrophy in order to partially or completely reverse the skeletal muscleatrophy that has occurred or to completely or partially block theoccurrence of further skeletal muscle atrophy would be therapeutictreatment of that subject. The term “therapeutic treatment” alsoincludes, for example, treatment of a subject not exhibiting signs ofskeletal muscle atrophy to induce skeletal muscle hypertrophy, e.g.,treatment of a livestock animal to increase muscle mass.

[0055] The term “treatment” means prophylactic or therapeutic treatment.

[0056] The Role of ARs in Regulation of Skeletal Muscle Mass

[0057] One of skill in the art would recognize the utility of thepresent invention given the information in the prior art and theteachings below. The results described herein demonstrate thatadministration of an AR agonist, amylin, blocks and/or inhibits theskeletal muscle atrophy inducing effect of denervation, disuse ordexamethasone treatment in models of skeletal muscle atrophy. Together,these data demonstrate the modulatory role of ARs in the process ofskeletal muscle atrophy. The specific role of ARs in vivo wasinvestigated using the pharmacological agent amylin which is a selectiveagonist for ARs in various models of skeletal muscle atrophy, describedhereinafter. Amylin has been well characterized and is described in thescientific literature.

[0058] FIGS. 1-3 show the results of experiments demonstrating thatadministration of amylin, a selective agonist of ARs, results instatistically significant inhibition of skeletal muscle atrophy andinduces skeletal muscle hypertrophy. Amylin administered twice daily incombination with the phosphodiesterase inhibitor, theophylline, resultedin inhibition of skeletal muscle atrophy in animal models of skeletalmuscle atrophy. Theophylline administered alone in these atrophy modelshad no effect, demonstrating that the anti-atrophy effect of amylin incombination with theophylline was due to the effect of amylin.Statistical significance of the results was determined using ANCOVA(Douglas C. Montgomery, Design and Analysis of Experiments, John Wileyand Sons, New York (2^(nd) ed. 1984)). Abbreviations used in FIGS. 1-3:g-gram; SEM-standard error of the mean.

[0059] Specifically, FIG. 1 (FIG. 1.) shows that amylin inhibitsdenervation-induced atrophy of the medial gastrocnemius muscle in amouse sciatic nerve denervation atrophy model. Legend: A—non-denervatedmedial gastrocnemius muscle from mice treated with physiological saline(non-atrophied control); B—denervated medial gastrocnemius muscle frommice treated with physiological saline (atrophied control); C—amylin(0.03 mg/kg)+theophylline; D—amylin (0.1 mg/kg)+theophylline; E—amylin(0.3 mg/kg)+theophylline. * —p≦0.05 compared to saline. Followingdenervation of the right sciatic nerve, male mice were injectedsubcutaneously in the midscapular region twice daily with amylin, at thedoses indicated above or vehicle control (physiological saline) for ninedays. Amylin was co-administered with twice daily intra-peritonealdosing of the phosphodiesterase inhibitor theophylline (30 mg/kg). Onday nine, the medial gastrocnemius muscle was removed and weighed todetermine the degree of atrophy.

[0060]FIG. 2 (FIG. 2.) demonstrates that amylin inhibitsglucocorticoid-induced muscle atrophy of the tibialis anterior (FIG. 2A)and medial gastrocnemius muscles (FIG. 2B) in the mouseglucocorticoid-induced atrophy model. Legend: A—water only with nodexamethasone included in drinking water (non-atrophied control);B—water+dexamethasone (atrophied control); C—amylin (0.3mg/kg/d)+theophylline+dexamethasone; D—amylin (1.0mg/kg/d)+theophylline+dexamethasone; *—p≦0.05 compared to water;#—p≦0.05 compared to water+dexamethasone. Following the addition of theglucocorticoid, dexamethasone, to the drinking water (1.2 mg/kg/d), malemice were injected subcutaneously in the midscapular region twice dailywith amylin, at the doses indicated above or vehicle control(physiological saline) for nine days. Amylin was co-administered withtwice daily intra-peritoneal dosing of the phosphodiesterase inhibitortheophylline (30 mg/kg). Nine days following the initiation of dosingamylin, the medial gastrocnemius and tibialis anterior muscles wereremoved and weighed to determine the degree of atrophy.

[0061]FIG. 3 (FIG. 3.) demonstrates that amylin inhibits disuse-inducedatrophy of the tibialis anterior (FIG. 3A) and medial gastrocnemius(FIG. 3B) muscles. In addition, statistically significant hypertrophy ofthe medial gastrocnemius and tibialis anterior muscles of the non-castedleg was also observed with amylin treatment. Legend: A—physiologicalsaline (control); B—amylin (0.1 mg/kg)+theophylline; C—amylin (0.3mg/kg)+theophylline; D—amylin (1.0 mg/kg)+theophylline; *—p≦0.05compared to saline. Following casting of the right hind leg, male micewere injected subcutaneously in the midscapular region twice daily, withamylin or vehicle control (physiological saline) for ten days at thedaily delivered dose indicated. Amylin was co-administered with twicedaily intra-peritoneal dosing of the phosphodiesterase inhibitortheophylline (30 mg/kg). On day ten, the medial gastrocnemius andtibialis anterior muscles were removed and weighed to determine thedegree of atrophy.

[0062] III. Preparation of ARs, Amylin or Amylin Analogs, or Cell LinesExpressing ARs

[0063] ARs, amylin and amylin analogs can be prepared for a variety ofuses, including, but not limited to, the generation of antibodies, useas reagents in the screening assays of the present invention, and use aspharmaceutical reagents for the treatment of skeletal muscle atrophy. Itwill be clear to one of skill in the art that, for certain embodimentsof the invention, purified polypeptides will be most useful, while forother embodiments cell lines expressing the polypeptides will be mostuseful. For example, in situations where it is important to retain thestructural and functional characteristics of the AR, e.g., in ascreening method to identify candidate compounds that activate ARs, itis desirable to use cells that express functional ARs.

[0064] Because amylin and amylin analogs are short polypeptides, theskilled artisan will recognize that these polypeptides will be mostconveniently provided by direct synthesis, rather than by recombinantmeans, using techniques well known in the art. In addition, many ofthese molecules are commercially available.

[0065] Where the source of ARs is a cell line expressing thepolypeptide, the cells may, for example, endogenously express AR, havebeen stimulated to increase endogenous AR expression or have beengenetically engineered to express an AR. Methods for determining whethera cell line expresses a polypeptide of interest are known in the art,for example, detection of the polypeptide with an appropriate antibody,use of a DNA probe to detect mRNA encoding the protein (e.g., northernblot or PCR techniques), or measuring binding of an agent selective forthe polypeptide of interest (e.g., a radiolabeled selective agonist).

[0066] The use of recombinant DNA technology in the preparation of ARs,or of cell lines expressing these polypeptides is particularlycontemplated. Such recombinant methods are well known in the art. Toexpress recombinant ARs, an expression vector that comprises a nucleicacid that encodes the polypeptides of interest under the control of oneor more regulatory elements, is prepared. Genomic or cDNA sequencesencoding ARs from several species have been described and are readilyavailable from the GenBank database or Derwent database as well as inthe sequence listing for this application. The accession numbers for ARsequences and corresponding SEQ ID NOS. are shown in Table I. Using thispublicly available sequence information, one means of isolating anucleic acid molecule encoding a CR, Ramp 1 or Ramp 3 component of an ARis to screen a genomic DNA or cDNA library with a natural orartificially synthesized DNA probe, using methods well known in the art,e.g., by PCR amplification of the sequence from an appropriate library.Another method is to use oligonucleotide primers specific for thereceptor of interest to PCR amplify the cDNA directly from mRNA isolatedfrom a particular tissue (such as skeletal muscle). Such isolated mRNAis commercially available. One of skill in the art would also recognizethat by using nucleic acid probes corresponding to portions of the knownAR receptor sequences the homologous cDNAs or genomic sequences fromother species can be obtained using known methods. Particularly usefulin the methods of the present invention are AR receptors from thespecies including, but not limited to, guinea pig, rabbit, pig, rat,mouse and turkey. By methods well known in the art, the isolated nucleicacid molecule encoding the AR of interest is then ligated into asuitable expression vector. The expression vector, thus prepared, isexpressed in a host cell and the host cells expressing the receptor areused directly in a screening assay or the receptor is isolated from thehost cells expressing the receptor and the isolated receptor is used ina screening assay.

[0067] The host-expression vector systems that may be used for purposesof the invention include, but are not limited to: microorganisms such asbacteria (e.g., E. coli, B. subtilis) transformed with recombinantbacteriophage DNA, plasmid DNA, or cosmid DNA expression vectorscontaining AR nucleotide sequences; yeast (e.g., Saccharomyces, Pichia)transformed with recombinant yeast expression vectors containing ARnucleotide sequences; insect cell systems infected with recombinantvirus expression vectors (e.g., baculovirus) containing AR nucleotidesequences; plant cell systems infected with recombinant virus expressionvectors (e.g., cauliflower mosaic virus, tobacco mosaic virus) ortransformed with recombinant plasmid expression vectors (e.g., Tiplasmid) containing AR nucleotide sequences; or mammalian cell systems(e.g., COS, CHO, HEK293, NIH3T3) harboring recombinant expressionconstructs containing promoters derived from the genome of mammaliancells (e.g., metallothionein promoter) or from mammalian viruses (e.g.,retrovirus LTR) and also containing AR nucleotide sequences.

[0068] The host cell is used to produce the polypeptides of interest.Because the AR contains a membrane bound molecule, it is purified fromthe host cell membranes or the AR is utilized while anchored in the cellmembrane, i.e., whole cells or membrane fractions of cells are used.Purification or enrichment of the ARs from such expression systems isaccomplished using appropriate detergents and lipid micelles by methodswell known to those skilled in the art.

[0069] In bacterial systems, a number of expression vectors may beadvantageously selected depending upon the use intended for the geneproduct being expressed. For example, when a large quantity of suchprotein is produced for the generation of antibodies to ARs, vectorsthat direct the expression of high levels of protein products aredesirable. One skilled in the art is able to generate such vectorconstructs and purify the proteins by a variety of methodologiesincluding selective purification technologies such as fusion proteinselective columns and antibody columns, and non-selective purificationtechnologies.

[0070] In an insect protein expression system, the baculovirus A.californica nuclear polyhedrosis virus (AcNPV), is used as a vector toexpress foreign genes in S. frugiperda cells. In this case, ARnucleotide sequences are cloned into non-essential regions of the virusand placed under the control of an AcNPV promoter. The recombinantviruses are then used to infect cells in which the inserted gene isexpressed and the protein is purified by one of many techniques known toone skilled in the art.

[0071] In mammalian host cells, a number of viral-based expressionsystems may be utilized. Utilization of these expression systems oftenrequires the creation of specific initiation signals in the vectors forefficient translation of the inserted nucleotide sequences. This isparticularly important if a portion of the AR gene is used which doesnot contain the endogenous initiation signal. The placement of thisinitiation signal, in frame with the coding region of the insertednucleotide sequence, as well as the addition of transcription andtranslation enhancing elements and the purification of the recombinantprotein, are achieved by one of many methodologies known to one skilledin the art. Also important in mammalian host cells is the selection ofan appropriate cell type that is capable of the necessaryposttranslational modifications of the recombinant protein. Suchmodifications, for example, cleavage, phosphorylation, glycosylation,etc., require the selection of the appropriate host cell that containsthe modifying enzymes. Such host cells include, but are not limited to,CHO, HEK293, NIH3T3, COS, etc. and are known by those skilled in theart.

[0072] For long term, high expression of recombinant proteins, stableexpression is preferred. For example, cell lines that stably express ARsmay be engineered. One of skill in the art, following known methods suchas electroporation, calcium phosphate transfection, or liposome-mediatedtransfection, can generate a cell line that stably expresses ARs. Thisis usually accomplished by transfecting cells using expression vectorsthat contain appropriate expression control elements (e.g., promotersequences, enhancer sequences, transcriptional termination sequences,polyadenylation sites, translational start sites, etc.), a selectablemarker, and the gene of interest. The selectable marker may either becontained within the same vector, as the gene of interest, or on aseparate vector, which is co-transfected with the AR sequence-containingvector. The selectable marker in the expression vector may conferresistance to the selection and allows cells to stably integrate thevector into their chromosomes and to grow to form foci that in turn canbe cloned and expanded into cell lines. Alternatively, the expressionvector may allow selection of the cell expressing the selectable markerutilizing a physical attribute of the marker, i.e., expression of GreenFluorescent Protein (GFP) allows for selection of cells expressing themarker using fluorescence activated cell sorting (FACS) analysis.

[0073] One of skill in the art is able to select an appropriate celltype for transfection in order to allow for selection of cells intowhich the gene of interest has been successfully integrated. Forexample, where the selectable marker is herpes simplex virus thymidinekinase, hypoxanthine-guanine phosphoribosyltransferase or adeninephosphoribosyltransferase, the appropriate cell type would be tk-,hgprt- or aprt- cells, respectively. Or, normal cells can be used wherethe selectable marker is dhfr, gpt, neo or hygro that confer resistanceto methotrexate, mycophenolic acid, G-418 or hygromycin, respectively.Such recombinant cell lines are useful for identification of candidatecompounds that affect the AR activity.

[0074] IV. Preparation of AR Antibodies

[0075] Antibodies that selectively recognize one or more epitopes of anAR are also encompassed by the invention. Such antibodies include, e.g.,polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanantibodies, single chain antibodies, Fab fragments, F(ab′)₂ fragments,molecules produced using a Fab expression library, human antibodies(polyclonal or monoclonal) produced in transgenic mice and epitopebinding fragments of any of the above. For therapeutic uses, chimeric orhuman antibodies are preferred; human antibodies are most preferred.

[0076] The antibodies can be utilized in conjunction with the compoundscreening schemes described herein for the evaluation of test compounds,e.g., for immobilization of AR polypeptides or such antibodies can beused in conjunction with gene therapy techniques to evaluate, forexample, the expression of ARs either in cells or directly in patienttissues in which these genes have been introduced. In addition,antibodies of the present invention are useful in the treatment ofskeletal muscle atrophy. Antibodies selective for the AR can be screenedby the methods of the present invention to identify a subset of theantibodies that are AR agonists. In addition, anti-idiotype antibodiesgenerated against antibodies specific for amylin or an amylin analog maybe useful as AR agonists and like anti-AR antibodies may be screened fortheir ability to activate the AR by methods of the present invention.

[0077] For the production of antibodies, a variety of host animals maybe immunized by injection with AR, amylin or an amylin analog,anti-amylin antibody, anti-amylin analog antibody, or immunogenicfragments thereof by methods well known in the art. For preparation ofan anti-idiotype antibody the immunogen is an anti-amylin antibody oranti-amylin analog antibody. Production of anti-idiotype antibodies isdescribed, for example, in U.S. Pat. No. 4,699,880, incorporated hereinby reference. Suitable host animals include, but are not limited to,rabbits, mice, goats, sheep and horses. Immunization techniques are wellknown in the art. Polyclonal antibodies can be purified from the serumof the immunized animals, or monoclonal antibodies can be generated bymethods that are well known in the art. These techniques include, butare not limited to, the well-known hybridoma techniques of Kohler andMilstein, human B-cell hybridoma techniques, and the EBV hybridomatechnology. Monoclonal antibodies may be of any immunoglobulin class,including IgG, IgE, IgM, IgA, and IgD containing either kappa or lambdalight chains.

[0078] Because of the immunogenicity of non-human antibodies in humans,chimeric antibodies are preferred to non-human antibodies when used fortherapeutic treatment of human patients. Techniques of producing andusing chimeric antibodies are known in the art, and are described in,for example, U.S. Pat. Nos. 5,807,715; 4,816,397; 4,816,567; 5,530,101;5,585,089; 5,693,761; 5,693,762; 6,180,370; and 5,824,307, allincorporated herein by reference.

[0079] Completely human antibodies are particularly desirable fortherapeutic treatment of human patients because they are lessimmunogenic than non-human antibodies or chimeric antibodies. Suchantibodies can be produced using transgenic mice which are substantiallyincapable of expressing endogenous immunoglobulin heavy and light chaingenes, but which can express human heavy and light chain genes. Thetransgenic mice are immunized in the normal fashion with a selectedantigen, e.g., all or a portion of ARs. Monoclonal antibodies directedagainst the antigen are obtained using conventional hybridoma technologyfrom these immunized transgenic mice. This technology is described indetail in U.S. Pat. Nos. 5,874,299; 5,877,397; 5,569,825; 5,661,016;5,770,429; and 6,075,181, all incorporated herein by reference. As analternative to obtaining human immunoglobulins directly from the cultureof the hybridoma cells, the hybridoma cells can be used as a source ofrearranged heavy chain and light chain loci for subsequent expression orgenetic manipulation. Isolation of genes from such antibody-producingcells is straightforward since high levels of the appropriate mRNAs areavailable. The recovered rearranged loci can be manipulated as desired.For example, the constant region can be eliminated or exchanged for thatof a different isotype or the variable regions can be linked to encodesingle chain Fv regions. Such techniques are described in WO 96/33735and WO 96/34096, all incorporated herein by reference.

[0080] V. Selection of Test Compounds

[0081] Compounds that can be screened in accordance with the assays ofthe invention include but are not limited to, libraries of knowncompounds, including natural products, such as plant or animal extracts,synthetic chemicals, biologically active materials including proteins,peptides such as soluble peptides, including but not limited to membersof random peptide libraries and combinatorial chemistry derivedmolecular library made of D- or L-configuration amino acids,phosphopeptides (including, but not limited to, members of random orpartially degenerate, directed phosphopeptide libraries), antibodies(including, but not limited to, polyclonal, monoclonal, chimeric, human,anti-idiotypic or single chain antibodies, and Fab, F(ab′)₂ and Fabexpression library fragments, and epitope-binding fragments thereof),organic and inorganic molecules.

[0082] In addition to the more traditional sources of test compounds,computer modeling and searching technologies permit the rationalselection of test compounds by utilizing structural information from theligand binding site of AR or from already identified agonists of ARs.Such rational selection of test compounds can decrease the number oftest compounds that must be screened in order to identify a candidatetherapeutic compound. ARs are GPCRs, and thus knowledge of the ARprotein sequences allows for the generation of a model of its bindingsite that can be used to screen for potential ligands. This process canbe accomplished in several manners well known in the art. Briefly, themost robust approach involves generating a sequence alignment of the ARsequences to a template (derived from the bacterio-rhodopsin orrhodopsin crystal structures or other GPCR model), conversion of theamino acid structures and refining the model by molecular mechanics andvisual examination. If a strong sequence alignment cannot be obtainedthen a model may also be generated by building models of the hydrophobichelices. These are then fitted together by rotating and translating eachhelix relative to the others starting from the general layout of theknown rhodopsin structures. Mutational data that point towardsresidue-residue contacts may also be used to position the helicesrelative to each other so that these contacts are achieved. During thisprocess, docking of the known ligands into the binding site cavitywithin the helices may also be used to help position the helices bydeveloping interactions that would stabilize the binding of the ligand.The model may be completed by refinement using molecular mechanics andloop building of the intracellular and extracellular loops usingstandard homology modeling techniques. General information regardingGPCR structure and modeling can be found in Schoneberg, T. et. al.,Molecular and Cellular Endocrinology, 151:181-193 (1999), Flower, D.,Biochimica et Biophysica Acta, 1422:207-234 (1999), and Sexton, P. M.,Current Opinion in Drug Discovery and Development, 2(5):440-448 (1999).

[0083] Once the model is completed, it can be used in conjunction withone of several existing computer programs to narrow the number ofcompounds to be screened by the screening methods of the presentinvention. The most general of these is the DOCK program (UCSF MolecularDesign Institute, 533 Parnassus Ave, U-64, Box 0446, San Francisco,Calif. 94143-0446). In several of its variants it can screen databasesof commercial and/or proprietary compounds for steric fit and roughelectrostatic complementarity to the binding site. It has frequentlybeen found that molecules that score well within DOCK have a betterchance of being ligands. Another program that can be used is FLEXX(Tripos Inc., 1699 South Hanley Rd., St. Louis, Mo.). This program,being significantly slower, is usually restricted to searches throughsmaller databases of compounds. The scoring scheme within FLEXX is moredetailed and usually gives a better estimate of binding ability thandoes DOCK. FLEXX is best used to confirm DOCK suggestions, or to examinelibraries of compounds that are generated combinatorially from knownligands or templates.

[0084] VI. Screening Assays to Identify Candidate Compounds for theRegulation of Skeletal Muscle Mass or Function

[0085] The finding that ARs plays a role in regulating skeletal muscleatrophy enables various methods of screening one or more test compoundsto identify candidate compounds that ultimately may be used forprophylactic or therapeutic treatment of skeletal muscle atrophy. Thisinvention provides methods for screening test compounds for theirability to bind to ARs, activate ARs, prolong or augment theagonist-induced activation of ARs or of a AR signal transduction pathwayor increase expression of AR or amylin genes.

[0086] For screening compounds which ultimately will be used to regulateskeletal muscle mass or function through ARs in humans, it is preferredthat the initial in vitro screen be carried out using either AR1 or AR2with an amino acid sequence that is greater than 78% identical to SEQ IDNO: 62 and more preferably greater than 90% identical to SEQ ID NO: 62.More preferably the test compounds will be screened against a human,mouse or rat AR, with the most preferable being human. For screeningcompounds which ultimately will be used to regulate skeletal muscle massor function through ARs in a non-human species it is preferable to usethe AR from the species in which treatment is contemplated.

[0087] The methods of the present invention are amenable to highthroughput applications; however, the use of as few as one test compoundin the method is encompassed by the term “screening”. Test compoundswhich bind to ARs, activate ARs, prolong or augment the agonist-inducedactivation of ARs or of an AR signal transduction pathway, or increaseexpression of AR or amylin genes, as determined by a method of thepresent invention, are referred to herein as “candidate compounds.” Suchcandidate compounds can be used to regulate skeletal muscle mass orfunction. However, more typically, this first level of in vitro screenprovides a means by which to select a narrower range of compounds, i.e.,the candidate compounds, which merit further investigation in additionallevels of screening. The skilled artisan will recognize that a utilityof the present invention is to identify, from a group of one or moretest compounds, a subset of compounds which merit further investigation.One of skill in the art will also recognize that the assays of thepresent invention are useful in ranking the probable usefulness of aparticular candidate compound relative to other candidate compounds. Forinstance, a candidate compound which activates AR at 1000 nM (but not at10 nM) is of less interest than one that activates AR at 10 nM. Usingsuch information the skilled artisan may select a subset of thecandidate compounds, identified in the first level of screening, forfurther investigation. By the way of example only, compounds whichactivate AR at concentrations of less than 200 nM might be furthertested in an animal model of skeletal muscle atrophy, whereas thoseabove that threshold would not be further tested. The skilled artisanwill also recognize that, depending on how the group of test compoundsis selected, and how the positive test compounds are selected, only acertain proportion of test compounds will be identified as candidatecompounds, and that this proportion may be very small.

[0088] The assay systems described below may be formulated into kitscomprising an AR or cells expressing an AR which can be packaged in avariety of containers, e.g., vials, tubes microtitre well plates,bottles and the like. Other reagents can be included in separatecontainers and provided with the kit, e.g., positive control samples,negative control samples, buffers and cell culture media.

[0089] In one embodiment, the invention provides a method for screeningone or more test compounds to identify candidate compounds that bind toan AR. Methods of determining binding of a compound to a receptor arewell known in the art. Typically, the assays include the steps ofincubating a source of an AR with a labeled compound, known to bind tothe receptor, in the presence or absence of a test compound anddetermining the amount of bound labeled compound. The source of the ARmay either be cells expressing an AR or some form of isolated AR, asdescribed herein. The labeled compound can be amylin or any amylinanalog labeled such that it can be measured, preferably quantitatively(e.g., ¹²⁵I-labeled, europium labeled, fluorescein labeled, GFP labeled,³⁵S-methionine labeled). Such methods of labeling are well known in theart. Test compounds that bind to an AR cause a reduction in the amountof labeled ligand bound to the receptor, thereby reducing the signallevel compared to that from control samples (absence of test compound).Variations of this technique have been described in which receptorbinding in the presence and absence of G-protein uncoupling agents candiscriminate agonists from antagonists (e.g., binding in the absence andpresence of a guanine nucleotide analog i.e., GpppNHp). See Keen, M.,Radioligand Binding Methods for Membrane Preparations and Intact cellsin Receptor Signal Transduction Protocols, R. A. J. Challis, (ed),Humana Press Inc., Totoway N.J. (1997).

[0090] Because it is desirable to discriminate between compounds thatbind specifically to an AR as compared to other related GPCRs, theassays described above should be conducted using a cell, or membranefrom a cell, which expresses only the AR or interest or the assays canbe conducted with a recombinant source of AR. Cells expressingadditional GPCRs that may interact with the AR ligands may be modifiedusing homologous recombination to inactivate or otherwise disable theGPCR gene. Alternatively, if the source of AR contains additional GPCRs,the background signal produced by the receptor that is not of interestmust be subtracted from the signal obtained in the assay. The backgroundresponse can be determined by a number of methods, including eliminationof the signal from the GPCR that is not of interest by use of antisense,antibodies or selective antagonists.

[0091] In another embodiment, the invention provides methods forscreening test compounds to identify candidate compounds that activateARs. Typically, the assays are cell-based; however, cell-free assays areknown which are able to differentiate agonist and antagonist binding asdescribed above. Cell-based assays include the steps of contacting cellswhich express an AR with a test compound or control and measuringactivation of the AR by measuring the expression or activity ofcomponents of the AR signal transduction pathways.

[0092] As described in the background section above, ARs appear tocouple through several different pathways, including the G_(αs) signaltransduction pathway, depending upon the cell type. It is thought thatagonist activation of an AR allows the receptor to signal via any ofthese pathways, provided that the necessary pathway components arepresent in the particular cell type. Thus, to screen for AR activation,an assay can use any of the signal transduction pathways as the readouteven if the relevant cell type for treatment, in vivo, couples AR toskeletal muscle atrophy via a different pathway. One of ordinary skillin the art would recognize that a screening assay would be effective foridentifying useful AR agonists independent of the pathway by whichreceptor activation was measured. Assays for measuring activation ofthese signaling pathways are known in the art.

[0093] For example, after contact with the test compound, lysates of thecells can be prepared and assayed for induction of cAMP. cAMP is inducedin response to G_(αs) activation. Because G_(αs) is activated byreceptors other than ARs and because a test compound may be exerting itseffect through ARs by another mechanism, two control comparisons arerelevant for determining whether a text compound increases levels ofcAMP via activation of an AR. One control compares the cAMP level ofcells contacted with a test compound and the cAMP level of cellscontacted with a control compound (i.e., the vehicle in which the testcompound is dissolved). If the test compound increases cAMP levelsrelative to the control compound this indicates that the test compoundis increasing cAMP by some mechanism. The other control compares thecAMP levels of an AR expressing cell line and a cell line that isessentially the same except that it does not express the AR, where bothof the cell lines have been treated with test compound. If the testcompound elevates cAMP levels in the AR expressing cell line relative tothe cell line that does not express ARs, this is an indication that thetest compound elevates cAMP via activation of the AR.

[0094] In a specific embodiment of the invention, cAMP induction ismeasured with the use of DNA constructs containing the cAMP responsiveelement linked to any of a variety of reporter genes can be introducedinto cells expressing ARs. Such reporter genes include, but are notlimited to, chloramphenicol acetyltransferase (CAT), luciferase,glucuronide synthetase, growth hormone, fluorescent proteins (e.g.,Green Fluorescent Protein), or alkaline phosphatase. Following exposureof the cells to the test compound, the level of reporter gene expressioncan be quantitated to determine the test compound's ability to increasecAMP levels and thus determine a test compounds ability to activate theAR.

[0095] The cells useful in this assay are the same as for the AR bindingassay described above, except that cells utilized in the activationassays preferably express a functional receptor which gives astatistically significant response to amylin or one or more amylinanalog. In addition to using cells expressing full length ARs, cells canbe engineered which express ARs containing the ligand binding domain ofthe receptor coupled to, or physically modified to contain, reporterelements or to interact with signaling proteins. For example, a wildtype AR or AR fragment can be fused to a G-protein resulting inactivation of the fused G-protein upon agonist binding to the AR portionof the fusion protein. (Siefert, R. et al., Trends Pharmacol. Sci. 20:383-389 (1999)). The cells should also preferably possess a number ofcharacteristics, depending on the readout, to maximize the inductiveresponse by amylin or the amylin analog, for example, for detecting astrong induction of a CRE reporter gene; (a) a low natural level ofcAMP; (b) G proteins capable of interacting with ARs; (c) a high levelof adenylyl cyclase; (d) a high level of protein kinase A; (e) a lowlevel of phosphodiesterases; and (f) a high level of cAMP responseelement binding protein would be advantageous. To increase the responseto amylin or an amylin analog, host cells could be engineered to expressa greater amount of favorable factors or a lesser amount of unfavorablefactors. In addition, alternative pathways for induction of the CREreporter could be eliminated to reduce basal levels.

[0096] In some instances, G protein-coupled receptor responses subside,or become desensitized, after prolonged exposure to an agonist. Anotherembodiment of the invention provides methods for identifying compoundsthat prolong or augment the agonist-induced activation of ARs, or the ARsignal transduction pathway, in response to an AR agonist. Suchcompounds may be used, for example, in conjunction with an AR agonistfor the treatment of skeletal muscle atrophy. Typically the method usesa cell based assay comprising in any order or concurrently (i)contacting the cells with a test compound; (ii) treating cellsexpressing functional AR with an AR agonist at a concentration ofagonist and for a period of agonist-receptor exposure sufficient toallow desensitization of the receptor; followed by (iii) determining thelevel of activation of the AR. One of skill in the art will recognizethat several mechanisms contribute to receptor desensitizationincluding, but not limited to, receptor phosphorylation, receptorinternalization or degradation and AR signal transduction pathwaydown-modulation. One of skill in the art can determine the appropriatetime (i.e., before, during or after agonist treatment) for contactingthe cells with the test compounds depending upon which mechanism ofdesensitization is targeted. For example, contacting the cells with testcompounds following agonist treatment, can detect test compounds whichblock receptor desensitization that occurs as a result ofphosphorylation of the receptor.

[0097] In another embodiment, the invention provides a method ofscreening one or more test compound to identify candidate compounds thatregulate transcription from an AR gene or regulate AR expression.Candidate compounds that regulate transcriptional activity of AR genesmay be identified using a reporter gene operably associated with an ARregulatory region (reporter gene construct). Such methods are known inthe art. In one such method, the reporter gene construct is contactedwith a test compound in the presence of a source of cellular factors andthe level of reporter gene expression is determined. A test compoundthat causes an increase in the level of expression, compared to acontrol sample, is indicative of a candidate compound that increasestranscription of an AR gene. To provide the cellular factors requiredfor in vitro or in vivo transcription, appropriate cells or cellextracts are prepared from any cell type that normally expresses an AR.

[0098] Candidate compounds that regulate an AR expression can also beidentified in a method wherein a cell is contacted with a test compoundand the expression of an AR is determined. The level of expression of anAR in the presence of the test compound is compared with the level ofexpression in the absence of the test compound. Test compounds thatincrease the expression of an AR are identified as candidate compoundsfor increasing muscle mass or muscle function. Such a method detectscandidate compounds which increase the transcription or translation ofan AR or which increase the stability of the mRNA or AR protein.

[0099] In another embodiment, this invention provides methods forscreening one or more test compounds to identify candidate compoundsthat regulate the expression of the amylin or an amylin analog. Suchassays are performed essentially as described above for the assays toidentify candidate compounds that regulate expression of ARs with thefollowing modifications. To identify candidate compound that regulatetranscription from the amylin gene or an amylin analog gene, thereporter gene is operably associated with the regulatory region of theamylin gene or amylin analog gene of interest and the source of cellularfactors should be from a cell type that expresses the gene of interest.

[0100] VII. Screening of Candidate Compounds using Models of SkeletalMuscle Atrophy

[0101] Candidate compounds selected from one or more test compounds byan in vitro assay, as described above, can be further tested for theirability to regulate skeletal muscle mass or function in model systems ofskeletal muscle atrophy and/or hypertrophy. Such models of skeletalmuscle atrophy or hypertrophy include both in vitro cell culture modelsand in vivo animal models of skeletal muscle atrophy. Such additionallevels of screening are useful to further narrow the range of candidatecompounds that merit additional investigation, e.g., clinical trials.

[0102] Cell Culture Models of Muscle Atrophy

[0103] In vitro models of skeletal muscle atrophy are known in the art.Such models are described, for example, in Vandenburgh, H. H., In Vitro24:609-619 (1988), Vandenburgh, H. H. et al., J of Biomechanics, 24Suppl 1:91-99 (1991), Vandenburgh, H. H et al., In Vitro Cell. Dev.Biol., 24(3):166-174 (1988), Chromiak, J. A., et al., In Vitro Cell.Dev. Biol. Anim., 34(9):694-703(1998), Shansky, J., et al., In VitroCell. Dev. Biol. Anim., 33(9):659-661 (1997), Perrone, C. E. et al., J.Biol. Chem. 270(5):2099-2106 (1995), Chromiac, J. A. and Vandenburgh, H.H., J. Cell. Physiol. 159(3):407-414 (1994), and Vandenburgh, H. H. andKarlisch, P., In Vitro Cell. Dev. Biol. 25(7):607-616 (1989). Suchmodels are useful, but not required, following the in vitro screeningdescribed above in order to further narrow the range of candidatecompounds that merit testing in an animal model. Cell culture models aretreated with candidate compounds and the response of the model to thetreatment is measured by assessing changes in muscle markers such as:muscle protein synthesis or degradation, changes in skeletal muscle massor contractile function. Those compounds that induce significant changesin the muscle markers are typically screened further in an animal modelof skeletal muscle atrophy.

[0104] Animal Models of Skeletal Muscle Atrophy

[0105] The candidate compounds are administered to non-human animals andthe response of the animals is monitored, for example, by assessingchanges in markers of atrophy or hypertrophy such as: skeletal musclemass, skeletal muscle function, muscle or myofiber cross-sectional area,contractile protein content, non-contractile protein content or abiochemical or genetic marker that correlates with skeletal muscle massor function changes. Candidate compounds that induce skeletal musclehypertrophy or prevent any aspect of skeletal muscle atrophy should beconsidered as prospective therapeutic candidates for treatment of humanskeletal muscle atrophy, and are referred to herein as candidatetherapeutic compounds. In addition to assessing the ability of acandidate compound to regulate skeletal muscle atrophy, undesirable sideeffects such as toxicity may also be detected in such a screen. Theabsence of unacceptably high levels of side effects may be used as afurther criterion for the selection of candidate therapeutic compounds.

[0106] A variety of animal models for skeletal muscle atrophy are knownin the art, such as those described in the following references:Herbison, G. J., et al. Arch. Phys. Med. Rehabil. 60:401-404 (1979),Appell, H-J. Sports Medicine 10:42-58 (1990), Hasselgren, P-O. andFischer, J. E. World J. Surg. 22:203-208 (1998), Agbenyega, E. T. andWareham, A. C. Comp. Biochem. Physiol. 102A:141-145 (1992), Thomason, D.B. and Booth, F. W. J. Appl. Physiol. 68:1-12 (1990), Fitts, R. H., etal. J. Appl. Physiol. 60:1946-1953 (1986), Bramanti, P., et al. Int. J.Anat. Embryol. 103:45-64 (1998), Cartee, G. D. J. Gerontol. A Biol. Sci.Med. Sci. 50:137-141 (1995), Cork, L. C., et al. Prog. Clin. Biol. Res.229:241-269 (1987), Booth, F. W. and Gollnick, P. D. Med. Sci. SportsExerc. 15:415-420 (1983), Bloomfield, S. A. Med. Sci. Sports Exerc.29:197-206 (1997). Preferred animals for these models are mice and rats.These models include, for example, models of disuse-induced atrophy suchas casting or otherwise immobilizing limbs, hind limb suspension,complete animal immobilization, and reduced gravity situations. Modelsof nerve damage induced atrophy include, for example, nerve crush,removal of sections of nerves that innervate specific muscles, toxinapplication to nerves and infection of nerves with viral, bacterial oreukaryotic infectious agents. Models of glucocorticoid-induced atrophyinclude application of atrophy-inducing doses of exogenousglucocorticoid to animals, and stimulation of endogenous corticosteroidproduction, for example, by application of hormones that activate thehypothalamus-pituitary-adrenal (HPA) axis. Models of sepsis-inducedatrophy include, for example, inoculation with sepsis-inducing organismssuch as bacteria, treatment of the animal with immune-activatingcompounds such as bacterial cell wall extract or endotoxin, and punctureof intestinal walls. Models of cachexia-induced atrophy include, forexample, inoculation of an animal with tumorigenic cells with cachexiaforming potential, infection of an animal with infectious agents (suchas viruses which cause AIDS) which result in cachexia and treatment ofan animal with hormones or cytokines such as CNTF, TNF, IL-6, IL-1, etc.which induce cachexia. Models of heart failure-induced atrophy includethe manipulation of an animal so that heart failure occurs withconcomitant skeletal muscle atrophy. Neurodegenerative disease-inducedatrophy models include autoimmune animal models such as those resultingfrom immunization of an animal with neuronal components. Musculardystrophy-induced models of atrophy include natural or man-madegenetically-induced models of muscular dystrophy such as the mutation ofthe dystrophin gene which occurs in the Mdx mouse.

[0107] Animal models of skeletal muscle hypertrophy include, forexample, models of increased limb muscle use due to inactivation of theopposing limb, reweighting following a disuse atrophy inducing event,reutilization of a muscle which atrophied because of transient nervedamage, increased use of selective muscles due to inactivation of asynergistic muscle (e.g., compensatory hypertrophy), increased muscleutilization due to increased load placed on the muscle and hypertrophyresulting from removal of the glucocorticoid afterglucocorticoid-induced atrophy. Preferred animal atrophy models includethe sciatic nerve denervation atrophy model, glucocorticoid-inducedatrophy model, and the leg casting disuse atrophy model that aredescribed in further detail below.

[0108] The sciatic nerve denervation atrophy model involvesanesthetizing the animal followed by the surgical removal of a shortsegment of either the right or left sciatic nerve, e.g., in mice thesciatic nerve is isolated approximately at the midpoint along the femurand a 3-5 mm segment is removed. This denervates the lower hind limbmusculature resulting in atrophy of these muscles. Typically,innervation to the biceps femoris is left intact to provide satisfactorymotion of the knee for virtually normal ambulation. Typically, inuntreated animals, muscle mass of the denervated muscles is reduced30-50% ten days following denervation. Following denervation, testcompounds are administered e.g., by injection or by continuous infusion,e.g., via implantation of an osmotic minipump (e.g., Alzet, Palo Alto,Calif.), to determine their effect on denervation induced skeletalmuscle atrophy. At various times following denervation, the animals areeuthanized and lower leg muscles are dissected rapidly from both thedenervated and nondenervated legs, the muscles, cleaned of tendons andconnective tissue, are weighed. The extent of atrophy in the affectedmuscles is analyzed, for example, by measuring muscle mass, musclecross-sectional area, myofiber cross-sectional area or contractileprotein content.

[0109] The glucocorticoid-induced atrophy model involves theadministration of a glucocorticoid to the test animal, e.g., 1.2mg/kg/day of dexamethasone in the drinking water. Typically, inuntreated animals, skeletal muscle mass is reduced 30-50% following tendays of dexamethasone administration. Concomitantly with, or followingglucocorticoid administration, test compounds are administered e.g., byinjection or by continuous infusion to determine their effect onglucocorticoid-induced skeletal muscle atrophy. At various timesfollowing glucocorticoid administration, the extent of atrophy in theaffected muscles is analyzed as described above for the denervationmodel.

[0110] The leg casting disuse atrophy model involves casting one hindleg of an animal from the knee down through the foot. Typically, musclemass is reduced 20-40% after ten days of casting. Following casting,test compounds are administered by injection or by continuous infusionvia implantation of an osmotic minipump (e.g., Alzet, Palo Alto, Calif.)to determine their effect on leg casting induced skeletal muscleatrophy. At various times following leg casting, the extent of atrophyin the affected muscles is analyzed as described above for thedenervation model.

[0111] One of skill in the art would recognize that in screening forcompounds for human use, because there are differences between the humanARs and the ARs from other animal species, there may be some falsepositive or negative results which arise when the screen is carried outusing non-human ARs. Thus, it is preferable to do the initial in vitroscreen using human ARs. In certain circumstances, identified candidatecompounds may be active toward only the human receptor and not toward anon-human receptor. In such circumstances, it may still be desirable todetermine whether these candidate compounds are able to regulateskeletal muscle mass or function in a second level of screening. Becausethese candidates do not activate non-human ARs, a standard in vivoscreen with non-human animal is not advised. In such circumstances thesecond level of screening for these candidates may be performed intransgenic animals that express human ARs.

[0112] Animals of any species, especially mammals, including, but notlimited to, mice, rats, rabbits, guinea pigs, pigs, goats, dogs andnon-human primates may be used to generate AR transgenic animals. Miceand rats are preferred, mice are most preferred. A variety of techniquesare known in the art and may be used to introduce the human ARtransgenes into animals to produce the founder lines of transgenicanimals. Such techniques include, but are not limited to, pronuclearmicroinjection, retrovirus-mediated gene transfer into germ lines, genetargeting in embryonic stem cells, electroporation of embryos andsperm-mediated gene transfer.

[0113] VIII. Gene Therapy Methods for the Treatment of Skeletal MuscleAtrophy

[0114] The overall activity of ARs can be increased by overexpressingthe genes for ARs (to increase expression of ARs) or a constitutivelyactive AR in the appropriate tissue. Amylin levels can be increased, invivo, by likewise overexpressing an amylin gene. Overexpression of thesegenes will increase the total cellular AR activity, thus, regulatingskeletal muscle atrophy. The gene or genes of interest are inserted intoa vector suitable for expression in the subject. These vectors include,but are not limited to, adenovirus, adenovirus associated virus,retrovirus and herpes virus vectors in addition to other particles thatintroduced DNA into cells (e.g., liposome, gold particles, etc.) or bydirect injection of the DNA expression vector, containing the gene ofinterest, into human tissue (e.g., muscle).

[0115] IX. Pharmaceutical Formulations and Methods for Use

[0116] Candidate compounds or candidate therapeutic compounds identifiedby screening methods described herein, can be administered toindividuals to treat skeletal muscle atrophy, or to induce skeletalmuscle hypertrophy. To this end, the present invention encompassesmethods and compositions for modulating skeletal muscle atrophy,including, but not limited to, skeletal muscle atrophy induced by disusedue to surgery, bed rest, broken bones; denervation/nerve damage due tospinal cord injury; autoimmune disease; infectious disease;glucocorticoid use for unrelated conditions; sepsis due to infection orother causes; nutrient limitation due to illness or starvation; cancercachexia; chronic inflammation; AIDS cachexia; COPD; congestive heartfailure; sarcopenia and genetic disorders; e.g., muscular dystrophies,neurodegenerative diseases. Agonists of ARs can be used to inhibitskeletal muscle atrophy. It is not necessary that effective compoundsdemonstrate absolute specificity for ARs. It is contemplated thatspecific antagonist of other affected receptors can be co-administeredwith an effective, but nonspecific, agonist. Alternately, this lack ofspecificity may be addressed by modulation of dose alone, or the dosingregimen.

[0117] The candidate compounds or candidate therapeutic compoundsidentified by the screening methods of the present invention may beadministered in conjunction with compounds which prolong or augment theactivation of ARs or of AR signal transduction pathways. These may beknown compounds, for example, theophylline, or these compounds may beidentified by the screening methods of this invention to prolong oraugment the activation of ARs or of AR signal transduction pathways.

[0118] Dose Determinations

[0119] Safety and therapeutic efficacy of compounds that agonize ARs canbe determined by standard procedures using either in vitro or in vivotechnologies. Compounds that exhibit large therapeutic indices arepreferred, although compounds with lower therapeutic indices are usefulif the level of side effects is acceptable. The data obtained from thein vitro and in vivo toxicological and pharmacological techniques can beused to formulate the human range of doses that may be useful. Thepreferred dose lies in the range in which the circulating concentrationof the compound is therapeutically maximal with acceptable safety. Thecirculating concentration of the compound may vary depending on the doseform, time after dosing, route of administration, etc. Doses outsidethis range are also useful provided the side effects are acceptable.Such matters as age and weight of the patient, and the like, can be usedto determine such matters in the conventional manner. Pharmacogeneticapproaches may be useful in optimizing compound selection, doses anddosing regimen in clinical populations.

[0120] Formulation and Use

[0121] Pharmaceutical compositions for use in the modulation of skeletalmuscle atrophy in accordance with the present invention may beformulated using conventional methodologies using pharmaceuticallyacceptable carriers and excipients. The compositions of this inventionare preferably provided in unit dosage form. As used herein, a “unitdosage form” is a composition of this invention containing an amount ofan AR agonist that is suitable for administration to an animal,preferably a mammal, more preferably a human subject, in a single dose,according to good medical practice. Pharmaceutical compositions may beformulated for delivery by, for example, intranasal, transdermal,inhalation, parenteral, cutaneous, oral or rectal administration. Fororal administration, the pharmaceutical composition may take the form oftablets or capsules containing the pharmacologically active compound andadditives including, but not limited to, binding agents, fillers,lubricants, disintegrants, or wetting agents. The tablets may be coated.Liquid preparations for oral administration include, but are not limitedto, syrups, suspensions or dry products which are reconstituted withliquid vehicle before use, containing the pharmacologically activecompound and additives including, but not limited to, suspending agents,emulsifying agents, non-aqueous vehicles, preservatives, buffer salts,flavoring, coloring, sweetening agents, etc. Pharmaceutical compositionsfor oral administration may be formulated for controlled release of thepharmacologically active compounds either in the mouth, stomach orintestinal tract.

[0122] For inhalation administration, the compounds for use according tothe present invention may be delivered by, but not limited to, thefollowing forms: liquid, powder, gel or in the form of an aerosol sprayutilizing either pressurized or non-pressurized propellants in eitherpremeasured or non-premeasured doses. The pharmacologically activecompound may be formulated with appropriate fillers, vehicles,preservatives, buffers, etc. For parenteral administration, thepharmacologically active compound may be formulated with acceptablephysiological carriers, preservatives, etc. and be prepared assuspensions, solutions, emulsion, powders ready for constitution, etc.for either bolus injection or infusion. Doses of these compounds may beadministered by a variety of technologies including hypodermic needles,high pressure devices, etc. For rectal administration, thepharmacologically active compound may be formulated with acceptablephysiological carriers, preservatives, etc. for delivery assuppositories, enemas, etc. For cutaneous administration, thepharmacologically active compound may be formulated with acceptablephysiological carriers including lotions, emollients, etc. orincorporated into a patch type device. For long term administration, thepharmacologically active compound and appropriate additives such as, butlimited to, polymers, hydrophobic materials, resins, etc. may beformulated as a depot preparation for either injection or implantationat multiple sites including but not limited to intramuscular andsubcutaneous locations. In addition, the pharmacologically activecompound may be administered by a dispensing device.

[0123] Monitoring of Effects During Clinical Trials

[0124] Monitoring the influence of compounds (e.g., drugs) on theexpression or activity of ARs can be employed not only in basic drugscreening, but also in clinical trials. For example, the effectivenessof a compound determined by a screening assay to increase AR receptoractivity or AR receptor expression can be assessed in clinical trials ofpatients with, or at risk for, skeletal muscle atrophy. At various timesfollowing administration of the test compound or placebo, the effect ofthe compound on the patient can be determined, for example, by observingthe change in skeletal muscle mass, skeletal muscle function,biochemical markers of muscle breakdown or quality of life measures.Methods of measuring skeletal muscle mass in human subjects are known inthe art and include, for example: measuring the girth of a limb;measuring muscle thickness with for instance, computer tomography, MRIor supersonics; or muscle biopsy to examine morphological andbiochemical parameters (e.g., cross-section fiber area, fiber diameteror enzyme activities). Furthermore, because skeletal muscle mass iscorrelated with skeletal muscle function, muscle function can be used asa surrogate marker of mass and muscle mass changes can be assessed usingfunctional measurements, e.g., strength, the force of a group ofsynergist muscles, or contraction characteristics found inelectromyographic recordings. In addition, muscle protein loss as aresult of muscle atrophy can be measured by quantitating levels of aminoacids or amino acids derivatives, i.e., 3-methyl histidine, in the urineor blood of a subject. For a review of such methods see Appell, SportsMed. 10:42-58 (1990). Quality of life measures include, but are notlimited to, the ease of getting out of a chair, number of steps takenbefore tiring or ability to climb stairs.

EXAMPLES Example 1

[0125] Construction of Vectors for Human AR (Human Calcitonin ReceptorAssociated with RAMP) Receptor Expression.

[0126] The human calcitonin receptor (hCR) DNA sequence, Accession No.X69920 (SEQ ID NO: 3), is retrieved and two oligonucleotides includingone containing the 5′ end of the gene beginning at the initiation codon(5′ oligonucleotide) and one containing the 3′ end of the genecontaining the stop codon (3′ oligonucleotide) are synthesized. Usingthe above 5′ and 3′ oligonucleotides, the hAR cDNA is amplified by PCRfrom the human skeletal muscle cDNA library available commercially usinga PCR kit. The hCR gene PCR product is purified and cloned into thepIRESneo vector (Clonetech Inc., Palo Alto, Calif., USA) by commerciallyavailable PCR cloning kit according to the manufacturer'srecommendations. pIRESneo/hCR is then used to transform competent E.coli cells. Plasmid DNA is isolated and insert from at least one cloneis sequenced to ensure that the hCR sequence is correct. HEK293 cellscontaining a stably integrated Mercury CRE-LUC plasmid (Clonetech Inc.,Palo Alto, Calif., USA) are transfected with purified pIRESneo/hCR DNA.Cells stably transfected with pIRESneo/hAR DNA are selected by culturingthe cells in G418. The stably transfected cells(HEK293/CRE-LUC/pIRESneo/hCR cells) are propagated in DMEM (LifeTechnologies, Rockville, Md.) containing 10% fetal bovine serum at 37°C. in a 5% carbon dioxide/95% air atmosphere. The clones are thencharacterized to ensure they have the correct Receptor ActivityModifying Protein (RAMP) profile to ensure high affinity amylinreceptors (RAMP1 or RAMP3). If the correct RAMPs are not expressed inthe cell line then the correct RAMP is expressed in a RAMP negative cellline along with the human calcitonin receptor so that high affinity hAR1and hAR2 can be expressed. The clones are characterized for both amylinbinding and CRE-LUC activation following exposure to amylin as describedin Example 2 and Example 3. Cells expressing the hAR receptor at anappropriate level and which are appropriately coupled to the CRE-LUCreporter system are then utilized for further analysis.

Example 2

[0127] Receptor Binding Assays

[0128] Receptor binding analysis of compounds is performed in wholecells by plating the HEK293/CRE-LUC/pIRESneo/hCR cells from Example 1 ina 96 well polylysine coated plate. Cells are seeded in DMEM mediumcontaining 10% fetal bovine serum at 37° C. in a 5% CO₂ and incubatedovernight. The culture medium is removed and the appropriate amount ofamylin covalently labeled with Europium (Eu-amylin) in MEM+10% Seablock(Clonetech Inc., Palo Alto, Calif., USA) is added. The cells areincubated with the Eu-amylin for 90 minutes at room temperature thenwashed 4 times with phosphate buffered saline lacking magnesium andcalcium. Following the final wash, enhancement solution is added and theplate is read on a plate reader. For saturation binding analysis, logdoses of Eu-amylin ranging from 10⁻¹² to 10⁻³ M are added to the cellsand binding analyzed both in the absence and the presence of asaturating concentration of unlabeled amylin for evaluation ofnon-specific binding. For competitive binding, a concentration ofEu-amylin is added which is half maximal, in terms of binding, inaddition to varying concentrations of the compound of interest.

Example 3

[0129] Receptor Activation Assay

[0130] Receptor activation analysis is performed by seeding theHEK293/CRE-LUC/pIRESneo/hCR cells of Example 1 into Packard ViewPlate-96 (Packard Inc., CA). Cells are seeded in DMEM containing 10%fetal bovine serum at 37° C. in a 5% CO₂ and incubated overnight. Themedium is then removed and replaced with DMEM containing 0.01% bovinealbumin fraction V containing the compound of interest. The cells arefurther incubated for four hours at 37° C. after which the medium isremoved and the cells are washed twice with Hanks Balanced Salt Solution(HBSS). Lysis Reagent is then added to the washed cells and incubatedfor 20 minutes at 37° C. The cells are then placed at −80° C. for 20minutes followed by a 20 minute incubation at 37° C. After thisincubation, Luciferase Assay Buffer and Luciferase Assay Substrate(Promega Inc., Madison, Wis.) are added to the cell lysates andluciferase activity quantitated using a luminometer. Relative activityof a compound is evaluated by comparing the increase following exposureto compound to the level of luciferase in HEK cells that contain theCRE-LUC construct without the hCR following exposure to compound.Specificity of response is also checked by evaluating luciferaseresponse of hCR/CRE-LUC HEK cells to compound in the presence andabsence of a 10-fold excess of hAR antagonist.

Example 4

[0131] Screen to Identify Candidate Compounds that Prolong or Augmentthe Activation of AR and/or an AR Receptor Signal Transduction Pathway.

[0132] Identification of compounds that prolong or augment theagonist-induced activation of the AR or of an AR signal transductionpathway, involves a variation of the Receptor Activation Assay describedin Example 3. Specifically, this assay is performed by seeding theHEK293/CRE-LUC/pIRESneo/hCR receptor cells into Packard View Plate-96(Packard Inc., CA). Cells are seeded in DMEM medium containing 10% fetalbovine serum and saturating amounts of amylin at 37° C. in a 5% CO₂ andincubated for 48 hours. The medium is then removed and replaced withDMEM containing 0.01% bovine albumin fraction V and amylin in additionto the compound of interest. The cells are then incubated for four hoursat 37° C. in a 5% CO₂ after which the medium is removed and the cellsare washed twice with HBSS. Cells are processed as in Example 3 andLuciferase Assay Buffer and Luciferase Assay Substrate are added to thecell lysates and luciferase activity is quantitated using a luminometer.Test compounds which stimulate fluorescence significantly above thelevels of control untreated cells, after correction for variations incell density, are considered candidate compounds for regulating skeletalmuscle mass or function. The compounds of most interest are those thatinduce relatively higher levels of fluorescence.

Example 5

[0133] Screen to Identify Candidate Compounds Specific for ARs.

[0134] Compounds that activate ARs are identified as in Example 3. Toselect those compounds that show selectivity for AR1 and AR2 over loweraffinity ARs, these compounds also are screened against lower affinityARs. HEK293/CRE-LUC/pIRESneo/human lower affinity ARs cells aregenerated essentially as described in Example 1 except that humancalcitonin receptor like receptor (hCRLR) DNA sequence, Accession No.X72304, is used for the initial PCR amplification. The human calcitoninreceptor is coexpressed in a cell line with RAMP2 or the humancalcitonin receptor like receptor is coexpressed in a cell line witheither RAMP1, RAMP2 or RAMP3 to generate the panel of lower affinityamylin receptors. To determine how active the compounds are againstlower affinity ARs, an activation assay is performed essentially asdescribed in Example 3 except that HEK293/CRE-LUC/pIRESneo/human loweraffinity AR cells are used to seed the plates. The amount offluorescence stimulated by the compound in AR expressing cells iscompared with the amount of fluorescence stimulated by the compound inlower affinity AR expressing cells. Those compounds which demonstrate a10-fold better response (on a molar basis) in AR expressing cells thanin lower affinity AR expressing cells are then checked further forspecificity of response to eliminate differences due to clonalvariation. HEK293/CRE-LUC/pIRESneo/hCR cells are assayed with thecompound in the presence or absence of a 10-fold excess of the ARantagonist, acetyl-amylin (8-37). Those compounds that show greater than10-fold selectivity for ARs and whose activity is inhibited byacetyl-amylin (8-37) are selected as candidate compounds.

Example 6

[0135] Screens to Identify Candidate Compounds that Increase hCR, RAMP,or Amylin Expression

[0136] The sequence containing the promoter region of either the humancalcitonin receptor gene, RAMP1 or RAMP3 genes, or amylin gene;beginning far enough upstream of the transcriptional initiation site tocontain all the regulatory elements necessary for physiologicalexpression of the gene in the appropriate tissue is retrieved from thehuman genome database. Two oligonucleotides, one containing the 5′ endof the promoter region (5′ oligonucleotide) and one containing the 3′end of the promoter region including the transcriptional start site (3′oligonucleotide) are synthesized. The 5′ and 3′ oligonucleotides areused for PCR amplification of the gene regulatory region from human DNAusing a PCR kit. The gene regulatory region PCR product is purified andcloned in a suitable commercially available vector. Competent E. colicells are transformed, and plasmid DNA is isolated, and the constructcontaining the gene regulatory region is analyzed by DNA sequencing toensure construct correctness and integrity. Purified plasmid DNAcontaining the gene regulatory region is then transfected into theHEK293 cells, clones are selected using G418, isolated and propagated inDMEM containing 10% FBS and G418 at 37° C. in a 5% CO₂. G418 resistantclones are characterized by Southern blotting to ensure that theycontain the gene regulatory promoter sequence; in addition activation ofthe gene regulatory region is analyzed using an appropriate stimulatingagent. Cells expressing the appropriate gene regulatory region-ECFP atan appropriate level are then used in assays designed to evaluatecompounds that can modulate the activity of the gene regulatory regionas follows. The regulatory region activation analysis is performed byseeding the gene regulatory region-ECFP containing HEK293 cells at anappropriate density into black with clear bottom 96 well microtiterplates and allowed to grow overnight. The following day, the medium isremoved and the test compound is added in fresh growth medium. The cellsare incubated for 16 hours at 37° C. in a 5% CO₂ followed by measurementof fluorescence (excitation at 433 (453) nm followed by detectingemission at 475 (501) nm using a fluorometer. Test compounds whichstimulate fluorescence significantly above the levels of controluntreated cells are considered candidate compounds for regulatingskeletal muscle mass or function.

Example 7

[0137] Determination of Absolute Force Measurement of a Muscle.

[0138] The extensor digitorum longus (EDL) and soleus muscles areremoved, tendon-to-tendon from the casted mouse leg. A silk suture istied to each tendon of the isolated muscles and the muscles are placedinto a Plexiglas chamber filled with Ringer solution (137 mM sodiumchloride, 24 mM sodium bicarbonate, 11 mM glucose, 5 mM potassiumchloride, 1 mM magnesium sulfate, 1 mM sodium phosphate, 0.025 mMtubocurarine, all at pH 7.4 and oxygenated with 95% oxygen/5% carbondioxide) constantly bubbled with 95% oxygen/5% carbon dioxide maintainedat 25° C. Muscles are aligned horizontally between a servomotor leverarm (Model 305B-LR Cambridge Technology Inc., Watertown Mass., USA) andthe stainless steel hook of a force transducer (Model BG-50; KuliteSemiconductor Products Inc., Leonia, N.J., USA) and field stimulated bypulses transmitted between two platinum electrodes placed longitudinallyon either side of the muscle. Square wave pulses (0.2 ms duration)generated by a personal computer with a Labview board (Model PCI-MIO16E-4), Labview Inc., Austin, Tex., USA) are amplified (Acurus poweramplifier model A25, Dobbs Ferry, N.Y., USA) to increase titaniccontraction. Stimulation voltage and muscle length (Lo) are adjusted toobtain maximum isometric twitch force. Maximum titanic force production(Po) is determined from the plateau of the frequency-force relationship.

Example 8

[0139] Therapeutic Treatment of Skeletal Muscle Atrophy using a HumanAntibody that is an Agonist of the hAR Receptor.

[0140] A human male subject weighing 50 kg and having significantmuscular atrophy of the arms and legs due to prolonged bed rest, istreated to reverse the skeletal muscle atrophy. Once each week for aperiod of 3 months, 15 mls of an aqueous solution of pH 6 comprising anactivating antibody of the hAR receptor is administered to the subjectvia intravenous injection. The solution comprises the following:Component Concentration (mg/ml) hAR receptor agonist antibody 20L-histidine HCl 0.47 L-histidine 0.3 α, α-trehalose dihydrate 20Polysorbate 20 0.1 Bacteriostatic Sterile water qs to 1 mL

[0141] At the end of the treatment period, the subject exhibitsmeasurable increases of muscle mass, strength and mobility of the armsand legs.

Example 9

[0142] Prophylactic Treatment of Skeletal Muscle Atrophy using a HumanAntibody that is an Agonist of the hAR Receptor.

[0143] A human female subject weighing 55 kg is scheduled for hip jointreplacement surgery in one month. The subject is treated to enhanceskeletal muscle mass prior to and following surgery to ultimately reducethe level of skeletal muscle atrophy due to muscle disuse duringpost-surgery recovery. Specifically, once each week for a period of 1month prior to surgery and for 2 months post-surgery, 18 ml of anaqueous solution of pH 6.0 comprising an activating antibody of the hARreceptor, is administered to the subject via intravenous injection. Thesolution comprises the following: Component Concentration (mg/ml) hARactivating antibody 20 L-histidine HCl 0.47 L-histidine 0.3 α,α-trehalose dihydrate 20 Polysorbate 20 0.1 Bacteriostatic Sterile waterqs to 1 mL

[0144] At the end of the treatment period, the subject exhibitsmeasurable preservation of muscle mass, strength and mobility of thearms and legs as compared to the subject's expected status withoutantibody therapy.

Example 13

[0145] Prophylactic Treatment of Skeletal Muscle Atrophy using Amylin.

[0146] A human female subject weighing 60 kg is admitted to the hospitalin a comatose state. The subject is treated by this method to preventatrophy of the skeletal muscle of the entire body due to disuse in thecomatose state. Specifically, once each day while in the coma, thesubject is administered, via slow intravenous infusion, approximately500 ml of an aqueous solution that is prepared by addition of 5 ml ofthe following stock solution to 500 ml of sterile saline: ComponentConcentration (mg/ml) Amylin 12 Sodium phosphate buffer, pH 7.4 140

[0147] As a result of treatment, the subject exhibits measurablepreservation of skeletal muscle mass and function, and reduced physicaltherapy needs during the coma and after regaining consciousness, ascompared to the subject's status without drug therapy.

[0148] Except as otherwise noted, all amounts including quantities,percentages, portions, and proportions, are understood to be modified bythe word “about”, and amounts are not intended to indicate significantdigits.

[0149] Except as otherwise noted, the articles “a”, “an”, and “the” mean“one or more”.

[0150] All documents cited in the Detailed Description of the Inventionare, in relevant part, incorporated herein by reference; the citation ofany document is not to be construed as an admission that it is prior artwith respect to the present invention.

[0151] While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

1 70 1 1530 DNA Homo sapiens CDS (73)..(1497) 1 ttgcttctat tgagctgtgcccagccgccc agtgacagaa ttccaggaca aagagatctt 60 caaaaaccaa aa atg agg ttcaca ttt aca agc cgg tgc ttg gca ctg ttt 111 Met Arg Phe Thr Phe Thr SerArg Cys Leu Ala Leu Phe 1 5 10 ctt ctt cta aat cac cca acc cca att cttcct gcc ttt tca aat caa 159 Leu Leu Leu Asn His Pro Thr Pro Ile Leu ProAla Phe Ser Asn Gln 15 20 25 acc tat cca aca ata gag ccc aag cca ttt ctttac gtc gta gga cga 207 Thr Tyr Pro Thr Ile Glu Pro Lys Pro Phe Leu TyrVal Val Gly Arg 30 35 40 45 aag aag atg atg gat gca cag tac aaa tgc tatgac cga atg cag cag 255 Lys Lys Met Met Asp Ala Gln Tyr Lys Cys Tyr AspArg Met Gln Gln 50 55 60 tta ccc gca tac caa gga gaa ggt cca tat tgc aatcgc acc tgg gat 303 Leu Pro Ala Tyr Gln Gly Glu Gly Pro Tyr Cys Asn ArgThr Trp Asp 65 70 75 gga tgg ctg tgc tgg gat gac aca ccg gct gga gta ttgtcc tat cag 351 Gly Trp Leu Cys Trp Asp Asp Thr Pro Ala Gly Val Leu SerTyr Gln 80 85 90 ttc tgc cca gat tat ttt ccg gat ttt gat cca tca gaa aaggtt aca 399 Phe Cys Pro Asp Tyr Phe Pro Asp Phe Asp Pro Ser Glu Lys ValThr 95 100 105 aaa tac tgt gat gaa aaa ggt gtt tgg ttt aaa cat cct gaaaac aat 447 Lys Tyr Cys Asp Glu Lys Gly Val Trp Phe Lys His Pro Glu AsnAsn 110 115 120 125 cga acc tgg tcc aac tat act atg tgc aat gct ttc actcct gag aaa 495 Arg Thr Trp Ser Asn Tyr Thr Met Cys Asn Ala Phe Thr ProGlu Lys 130 135 140 ctg aag aat gca tat gtt ctg tac tat ttg gct att gtgggt cat tct 543 Leu Lys Asn Ala Tyr Val Leu Tyr Tyr Leu Ala Ile Val GlyHis Ser 145 150 155 ttg tca att ttc acc cta gtg att tcc ctg ggg att ttcgtg ttt ttc 591 Leu Ser Ile Phe Thr Leu Val Ile Ser Leu Gly Ile Phe ValPhe Phe 160 165 170 agg agc ctt ggc tgc caa agg gta acc ctg cac aag aacatg ttt ctt 639 Arg Ser Leu Gly Cys Gln Arg Val Thr Leu His Lys Asn MetPhe Leu 175 180 185 act tac att ctg aat tct atg att atc atc atc cac ctggtt gaa gta 687 Thr Tyr Ile Leu Asn Ser Met Ile Ile Ile Ile His Leu ValGlu Val 190 195 200 205 gta ccc aat gga gag ctc gtg cga agg gac ccg gtgagc tgc aag att 735 Val Pro Asn Gly Glu Leu Val Arg Arg Asp Pro Val SerCys Lys Ile 210 215 220 ttg cat ttt ttc cac cag tac atg atg gcc tgc aactat ttc tgg atg 783 Leu His Phe Phe His Gln Tyr Met Met Ala Cys Asn TyrPhe Trp Met 225 230 235 ctc tgt gaa ggg atc tat ctt cat aca ctc att gtcgtg gct gtg ttt 831 Leu Cys Glu Gly Ile Tyr Leu His Thr Leu Ile Val ValAla Val Phe 240 245 250 act gag aag caa cgc ttg cgg tgg tat tat ctc ttgggc tgg ggg ttc 879 Thr Glu Lys Gln Arg Leu Arg Trp Tyr Tyr Leu Leu GlyTrp Gly Phe 255 260 265 ccg ctg gtg cca acc act atc cat gct att acc agggcc gtg tac ttc 927 Pro Leu Val Pro Thr Thr Ile His Ala Ile Thr Arg AlaVal Tyr Phe 270 275 280 285 aat gac aac tgc tgg ctg agt gtg gaa acc catttg ctt tac ata atc 975 Asn Asp Asn Cys Trp Leu Ser Val Glu Thr His LeuLeu Tyr Ile Ile 290 295 300 cat gga cct gtc atg gcg gca ctt gtg gtc aatttc ttc ttt ttg ctc 1023 His Gly Pro Val Met Ala Ala Leu Val Val Asn PhePhe Phe Leu Leu 305 310 315 aac att gtc cgg gtg ctt gtg acc aaa atg agggaa acc cat gag gcg 1071 Asn Ile Val Arg Val Leu Val Thr Lys Met Arg GluThr His Glu Ala 320 325 330 gaa tcc cac atg tac ctg aag gct gtg aag gccacc atg atc ctt gtg 1119 Glu Ser His Met Tyr Leu Lys Ala Val Lys Ala ThrMet Ile Leu Val 335 340 345 ccc ctg ctg gga atc cag ttt gtc gtc ttt ccctgg aga cct tcc aac 1167 Pro Leu Leu Gly Ile Gln Phe Val Val Phe Pro TrpArg Pro Ser Asn 350 355 360 365 aag atg ctt ggg aag ata tat gat tac gtgatg cac tct ctg att cat 1215 Lys Met Leu Gly Lys Ile Tyr Asp Tyr Val MetHis Ser Leu Ile His 370 375 380 ttc cag ggc ttc ttt gtt gcg acc atc tactgc ttc tgc aac aat gag 1263 Phe Gln Gly Phe Phe Val Ala Thr Ile Tyr CysPhe Cys Asn Asn Glu 385 390 395 gtc caa acc acc gtg aag cgc caa tgg gcccaa ttc aaa att cag tgg 1311 Val Gln Thr Thr Val Lys Arg Gln Trp Ala GlnPhe Lys Ile Gln Trp 400 405 410 aac cag cgt tgg ggg agg cgc ccc tcc aaccgc tct gct cgc gct gca 1359 Asn Gln Arg Trp Gly Arg Arg Pro Ser Asn ArgSer Ala Arg Ala Ala 415 420 425 gcc gct gct gcg gag gct ggc gac atc ccaatt tac atc tgc cat cag 1407 Ala Ala Ala Ala Glu Ala Gly Asp Ile Pro IleTyr Ile Cys His Gln 430 435 440 445 gag ccg agg aat gaa cca gcc aac aaccaa ggc gag gag agt gct gag 1455 Glu Pro Arg Asn Glu Pro Ala Asn Asn GlnGly Glu Glu Ser Ala Glu 450 455 460 atc atc cct ttg aat atc ata gag caagag tca tct gct tga 1497 Ile Ile Pro Leu Asn Ile Ile Glu Gln Glu Ser SerAla 465 470 atgtgaagca aacacagtat cgtgatcact gag 1530 2 474 PRT Homosapiens 2 Met Arg Phe Thr Phe Thr Ser Arg Cys Leu Ala Leu Phe Leu LeuLeu 1 5 10 15 Asn His Pro Thr Pro Ile Leu Pro Ala Phe Ser Asn Gln ThrTyr Pro 20 25 30 Thr Ile Glu Pro Lys Pro Phe Leu Tyr Val Val Gly Arg LysLys Met 35 40 45 Met Asp Ala Gln Tyr Lys Cys Tyr Asp Arg Met Gln Gln LeuPro Ala 50 55 60 Tyr Gln Gly Glu Gly Pro Tyr Cys Asn Arg Thr Trp Asp GlyTrp Leu 65 70 75 80 Cys Trp Asp Asp Thr Pro Ala Gly Val Leu Ser Tyr GlnPhe Cys Pro 85 90 95 Asp Tyr Phe Pro Asp Phe Asp Pro Ser Glu Lys Val ThrLys Tyr Cys 100 105 110 Asp Glu Lys Gly Val Trp Phe Lys His Pro Glu AsnAsn Arg Thr Trp 115 120 125 Ser Asn Tyr Thr Met Cys Asn Ala Phe Thr ProGlu Lys Leu Lys Asn 130 135 140 Ala Tyr Val Leu Tyr Tyr Leu Ala Ile ValGly His Ser Leu Ser Ile 145 150 155 160 Phe Thr Leu Val Ile Ser Leu GlyIle Phe Val Phe Phe Arg Ser Leu 165 170 175 Gly Cys Gln Arg Val Thr LeuHis Lys Asn Met Phe Leu Thr Tyr Ile 180 185 190 Leu Asn Ser Met Ile IleIle Ile His Leu Val Glu Val Val Pro Asn 195 200 205 Gly Glu Leu Val ArgArg Asp Pro Val Ser Cys Lys Ile Leu His Phe 210 215 220 Phe His Gln TyrMet Met Ala Cys Asn Tyr Phe Trp Met Leu Cys Glu 225 230 235 240 Gly IleTyr Leu His Thr Leu Ile Val Val Ala Val Phe Thr Glu Lys 245 250 255 GlnArg Leu Arg Trp Tyr Tyr Leu Leu Gly Trp Gly Phe Pro Leu Val 260 265 270Pro Thr Thr Ile His Ala Ile Thr Arg Ala Val Tyr Phe Asn Asp Asn 275 280285 Cys Trp Leu Ser Val Glu Thr His Leu Leu Tyr Ile Ile His Gly Pro 290295 300 Val Met Ala Ala Leu Val Val Asn Phe Phe Phe Leu Leu Asn Ile Val305 310 315 320 Arg Val Leu Val Thr Lys Met Arg Glu Thr His Glu Ala GluSer His 325 330 335 Met Tyr Leu Lys Ala Val Lys Ala Thr Met Ile Leu ValPro Leu Leu 340 345 350 Gly Ile Gln Phe Val Val Phe Pro Trp Arg Pro SerAsn Lys Met Leu 355 360 365 Gly Lys Ile Tyr Asp Tyr Val Met His Ser LeuIle His Phe Gln Gly 370 375 380 Phe Phe Val Ala Thr Ile Tyr Cys Phe CysAsn Asn Glu Val Gln Thr 385 390 395 400 Thr Val Lys Arg Gln Trp Ala GlnPhe Lys Ile Gln Trp Asn Gln Arg 405 410 415 Trp Gly Arg Arg Pro Ser AsnArg Ser Ala Arg Ala Ala Ala Ala Ala 420 425 430 Ala Glu Ala Gly Asp IlePro Ile Tyr Ile Cys His Gln Glu Pro Arg 435 440 445 Asn Glu Pro Ala AsnAsn Gln Gly Glu Glu Ser Ala Glu Ile Ile Pro 450 455 460 Leu Asn Ile IleGlu Gln Glu Ser Ser Ala 465 470 3 3331 DNA Homo sapiens CDS (38)..(1462)3 cagaattcca ggacaaagag atcttcaaaa atcaaaa atg agg ttc aca ttt aca 55Met Arg Phe Thr Phe Thr 1 5 agc cgg tgc ttg gca ctg ttt ctt ctt cta aatcac cca acc cca att 103 Ser Arg Cys Leu Ala Leu Phe Leu Leu Leu Asn HisPro Thr Pro Ile 10 15 20 ctt cct gcc ttt tca aat caa acc tat cca aca atagag ccc aag cca 151 Leu Pro Ala Phe Ser Asn Gln Thr Tyr Pro Thr Ile GluPro Lys Pro 25 30 35 ttt ctt tac gtc gta gga cga aag aag atg atg gat gcacag tac aaa 199 Phe Leu Tyr Val Val Gly Arg Lys Lys Met Met Asp Ala GlnTyr Lys 40 45 50 tgc tat gac cga atg cag cag tta ccc gca tac caa gga gaaggt cca 247 Cys Tyr Asp Arg Met Gln Gln Leu Pro Ala Tyr Gln Gly Glu GlyPro 55 60 65 70 tat tgc aat cgc acc tgg gat gga tgg ctg tgc tgg gat gacaca ccg 295 Tyr Cys Asn Arg Thr Trp Asp Gly Trp Leu Cys Trp Asp Asp ThrPro 75 80 85 gct gga gta ttg tcc tat cag ttc tgc cca gat tat ttt ccg gatttt 343 Ala Gly Val Leu Ser Tyr Gln Phe Cys Pro Asp Tyr Phe Pro Asp Phe90 95 100 gat cca tca gaa aag gtt aca aaa tac tgt gat gaa aaa ggt gtttgg 391 Asp Pro Ser Glu Lys Val Thr Lys Tyr Cys Asp Glu Lys Gly Val Trp105 110 115 ttt aaa cat cct gaa aac aat cga acc tgg tcc aac tat act atgtgc 439 Phe Lys His Pro Glu Asn Asn Arg Thr Trp Ser Asn Tyr Thr Met Cys120 125 130 aat gct ttc act cct gag aaa ctg aag aat gca tat gtt ctg tactat 487 Asn Ala Phe Thr Pro Glu Lys Leu Lys Asn Ala Tyr Val Leu Tyr Tyr135 140 145 150 ttg gct att gtg ggt cat tct ttg tca att ttc acc cta gtgatt tcc 535 Leu Ala Ile Val Gly His Ser Leu Ser Ile Phe Thr Leu Val IleSer 155 160 165 ctg ggg att ttc gtg ttt ttc agg agc ctt ggc tgc caa agggta acc 583 Leu Gly Ile Phe Val Phe Phe Arg Ser Leu Gly Cys Gln Arg ValThr 170 175 180 ctg cac aag aac atg ttt ctt act tac att ctg aat tct atgatt atc 631 Leu His Lys Asn Met Phe Leu Thr Tyr Ile Leu Asn Ser Met IleIle 185 190 195 atc atc cac ctg gtt gaa gta gta ccc aat gga gag ctc gtgcga agg 679 Ile Ile His Leu Val Glu Val Val Pro Asn Gly Glu Leu Val ArgArg 200 205 210 gac ccg gtg agc tgc aag att ttg cat ttt ttc cac cag tacatg atg 727 Asp Pro Val Ser Cys Lys Ile Leu His Phe Phe His Gln Tyr MetMet 215 220 225 230 gcc tgc aac tat ttc tgg atg ctc tgt gaa ggg atc tatctt cat aca 775 Ala Cys Asn Tyr Phe Trp Met Leu Cys Glu Gly Ile Tyr LeuHis Thr 235 240 245 ctc att gtc gtg gct gtg ttt act gag aag caa cgc ttgcgg tgg tat 823 Leu Ile Val Val Ala Val Phe Thr Glu Lys Gln Arg Leu ArgTrp Tyr 250 255 260 tat ctc ttg ggc tgg ggg ttc ccg ctg gtg cca acc actatc cat gct 871 Tyr Leu Leu Gly Trp Gly Phe Pro Leu Val Pro Thr Thr IleHis Ala 265 270 275 att acc agg gcc gtg tac ttc aat gac aac tgc tgg ctgagt gtg gaa 919 Ile Thr Arg Ala Val Tyr Phe Asn Asp Asn Cys Trp Leu SerVal Glu 280 285 290 acc cat ttg ctt tac ata atc cat gga cct gtc atg gcggca ctt gtg 967 Thr His Leu Leu Tyr Ile Ile His Gly Pro Val Met Ala AlaLeu Val 295 300 305 310 gtc aat ttc ttc ttt ttg ctc aac att gtc cgg gtgctt gtg acc aaa 1015 Val Asn Phe Phe Phe Leu Leu Asn Ile Val Arg Val LeuVal Thr Lys 315 320 325 atg agg gaa acc cat gag gcg gaa tcc cac atg tacctg aag gct gtg 1063 Met Arg Glu Thr His Glu Ala Glu Ser His Met Tyr LeuLys Ala Val 330 335 340 aag gcc acc atg atc ctt gtg ccc ctg ctg gga atccag ttt gtc gtc 1111 Lys Ala Thr Met Ile Leu Val Pro Leu Leu Gly Ile GlnPhe Val Val 345 350 355 ttt ccc tgg aga cct tcc aac aag atg ctt ggg aagata tat gat tac 1159 Phe Pro Trp Arg Pro Ser Asn Lys Met Leu Gly Lys IleTyr Asp Tyr 360 365 370 gtg atg cac tct ctg att cat ttc cag ggc ttc tttgtt gcg acc atc 1207 Val Met His Ser Leu Ile His Phe Gln Gly Phe Phe ValAla Thr Ile 375 380 385 390 tac tgc ttc tgc aac aat gag gtc caa acc accgtg aag cgc caa tgg 1255 Tyr Cys Phe Cys Asn Asn Glu Val Gln Thr Thr ValLys Arg Gln Trp 395 400 405 gcc caa ttc aaa att cag tgg aac cag cgt tggggg agg cgc ccc tcc 1303 Ala Gln Phe Lys Ile Gln Trp Asn Gln Arg Trp GlyArg Arg Pro Ser 410 415 420 aac cgc tct gct cgc gct gca gcc gct gct gcggag gct ggc gac atc 1351 Asn Arg Ser Ala Arg Ala Ala Ala Ala Ala Ala GluAla Gly Asp Ile 425 430 435 cca att tac atc tgc cat cag gag ctg agg aatgaa cca gcc aac aac 1399 Pro Ile Tyr Ile Cys His Gln Glu Leu Arg Asn GluPro Ala Asn Asn 440 445 450 caa ggc gag gag agt gct gag atc atc cct ttgaat atc ata gag caa 1447 Gln Gly Glu Glu Ser Ala Glu Ile Ile Pro Leu AsnIle Ile Glu Gln 455 460 465 470 gag tca tct gct tga atgtgaaggcaaacacagca tcgtgatcac tgagccatca 1502 Glu Ser Ser Ala tttcctgggagaaagaccat gcatttaaag tattctccat cctcccagga accgaacata 1562 tcatttgtgaagaattattc agtgaatttg tccattgtaa atctgaagaa agttattctt 1622 ggtactgttgctttgggaga cagtctagga atggagtctc ccactgcaac ttgtgaactc 1682 catcattcatccaggactga gatgcaaatg tcacagtaat gcaagcaaag tatcaaagaa 1742 aaacaatgaaattgacctag ttcagataca gggtgctcct tgtcaatact gagccattta 1802 tacctttgaaatattaaaat cactgtcaat atttttattt ttaactctgg attttgaatt 1862 agattatttctgtatttggc tatggatctg atttttaatt tttttaaatt tcagtcaatt 1922 ctgatgttactgagatgttt taccatcctt acaatgtaaa ccacatgaac tacgtgacct 1982 ctgcaagacaaagcggcttt ctaatagaga gattagtaaa tatgtgaaga aaaagacctg 2042 catttggcaggaagatgtat gctttgaatg caaaagaaat ttagagtcaa tttgctgaaa 2102 acattacatgctcagcttgg ttttggacaa gcctgtccat tgggcaggac ctagctgttg 2162 taaagaattggtcttaatgt tgaatgtatt ttggttgctg atgtttataa actgagaggt 2222 cacaaagaatctatcactaa aaatttttac aaaactgcca aaaatataat tcttagtgga 2282 agacaatactccctttaaag agagtttgcc actcccctaa actccaggat ttataaagca 2342 aattactccaaggtttataa agcagattac ctcttgccct tgggtgctat ctagcagtaa 2402 aagataaatttgttgaatat tggtaattaa aagactccac ataagtccat taactgcttt 2462 ccacccagcttcaaagctta aaaagagctc aggcttttcc aggaagatcc aggagggcta 2522 attagaaatcaacttgtggt tgaccgcttg tttcttgtta ttaccaaaca ggaggggaaa 2582 aaattaactgctccaaattt aaccataaat caattcatgt ttaacgtttc tcattaaaat 2642 ccagtattatattatcatat ctctctttac ttcccagtat aagatttttg aaaatcctga 2702 ataaaccagtatcgttactg gcacctgaaa ttaatttgtg aatttgcaac agtaatcaga 2762 gttaccattatttaatttgt atgctaaatg aggaggtaca ttgaaaccct ccaaatctcc 2822 agtctcatctatgtcatatt ttgccactgc ctttcagaag tgatttagtt gtggaaagat 2882 aataaattgatttgttatgg ttacatattt agcgcaccca gagaaaatta attatatttc 2942 tacagagaaaatgaatttgg gatactaaag tagtttaagt ctcctttact gaatgtaagg 3002 gggggatcgaaaagaaggta tttttccaat cacagtgtta tgtagtattg ttctattttt 3062 gtttacaaacatggaaaaca gagtatttct ggcagctgtg gtacaaatgt gataatatat 3122 tgctaaaatattttagatgt tattatgcta atatagtagg ggttgaagaa aacaaaatag 3182 cttattatagaattgcacat agttctgccc aaattatgtg aaatgcttat gcttgtgtat 3242 atgtataaattaatacagag tacgttaaaa gcaaaaagat gtatatttgc atatttttct 3302 aaagaaatatattattcatc ttttcattc 3331 4 474 PRT Homo sapiens 4 Met Arg Phe Thr PheThr Ser Arg Cys Leu Ala Leu Phe Leu Leu Leu 1 5 10 15 Asn His Pro ThrPro Ile Leu Pro Ala Phe Ser Asn Gln Thr Tyr Pro 20 25 30 Thr Ile Glu ProLys Pro Phe Leu Tyr Val Val Gly Arg Lys Lys Met 35 40 45 Met Asp Ala GlnTyr Lys Cys Tyr Asp Arg Met Gln Gln Leu Pro Ala 50 55 60 Tyr Gln Gly GluGly Pro Tyr Cys Asn Arg Thr Trp Asp Gly Trp Leu 65 70 75 80 Cys Trp AspAsp Thr Pro Ala Gly Val Leu Ser Tyr Gln Phe Cys Pro 85 90 95 Asp Tyr PhePro Asp Phe Asp Pro Ser Glu Lys Val Thr Lys Tyr Cys 100 105 110 Asp GluLys Gly Val Trp Phe Lys His Pro Glu Asn Asn Arg Thr Trp 115 120 125 SerAsn Tyr Thr Met Cys Asn Ala Phe Thr Pro Glu Lys Leu Lys Asn 130 135 140Ala Tyr Val Leu Tyr Tyr Leu Ala Ile Val Gly His Ser Leu Ser Ile 145 150155 160 Phe Thr Leu Val Ile Ser Leu Gly Ile Phe Val Phe Phe Arg Ser Leu165 170 175 Gly Cys Gln Arg Val Thr Leu His Lys Asn Met Phe Leu Thr TyrIle 180 185 190 Leu Asn Ser Met Ile Ile Ile Ile His Leu Val Glu Val ValPro Asn 195 200 205 Gly Glu Leu Val Arg Arg Asp Pro Val Ser Cys Lys IleLeu His Phe 210 215 220 Phe His Gln Tyr Met Met Ala Cys Asn Tyr Phe TrpMet Leu Cys Glu 225 230 235 240 Gly Ile Tyr Leu His Thr Leu Ile Val ValAla Val Phe Thr Glu Lys 245 250 255 Gln Arg Leu Arg Trp Tyr Tyr Leu LeuGly Trp Gly Phe Pro Leu Val 260 265 270 Pro Thr Thr Ile His Ala Ile ThrArg Ala Val Tyr Phe Asn Asp Asn 275 280 285 Cys Trp Leu Ser Val Glu ThrHis Leu Leu Tyr Ile Ile His Gly Pro 290 295 300 Val Met Ala Ala Leu ValVal Asn Phe Phe Phe Leu Leu Asn Ile Val 305 310 315 320 Arg Val Leu ValThr Lys Met Arg Glu Thr His Glu Ala Glu Ser His 325 330 335 Met Tyr LeuLys Ala Val Lys Ala Thr Met Ile Leu Val Pro Leu Leu 340 345 350 Gly IleGln Phe Val Val Phe Pro Trp Arg Pro Ser Asn Lys Met Leu 355 360 365 GlyLys Ile Tyr Asp Tyr Val Met His Ser Leu Ile His Phe Gln Gly 370 375 380Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn Asn Glu Val Gln Thr 385 390395 400 Thr Val Lys Arg Gln Trp Ala Gln Phe Lys Ile Gln Trp Asn Gln Arg405 410 415 Trp Gly Arg Arg Pro Ser Asn Arg Ser Ala Arg Ala Ala Ala AlaAla 420 425 430 Ala Glu Ala Gly Asp Ile Pro Ile Tyr Ile Cys His Gln GluLeu Arg 435 440 445 Asn Glu Pro Ala Asn Asn Gln Gly Glu Glu Ser Ala GluIle Ile Pro 450 455 460 Leu Asn Ile Ile Glu Gln Glu Ser Ser Ala 465 4705 1425 DNA Homo sapiens CDS (1)..(1425) 5 atg agg ttc aca ttt aca agccgg tgc ttg gca ctg ttt ctt ctt cta 48 Met Arg Phe Thr Phe Thr Ser ArgCys Leu Ala Leu Phe Leu Leu Leu 1 5 10 15 aat cac cca acc cca att cttcct gcc ttt tca aat caa acc tat cca 96 Asn His Pro Thr Pro Ile Leu ProAla Phe Ser Asn Gln Thr Tyr Pro 20 25 30 aca ata gag ccc aag cca ttt ctttac gtc gta gga cga aag aag atg 144 Thr Ile Glu Pro Lys Pro Phe Leu TyrVal Val Gly Arg Lys Lys Met 35 40 45 atg gat gca cag tac aaa tgc tat gaccga atg cag cag tta ccc gca 192 Met Asp Ala Gln Tyr Lys Cys Tyr Asp ArgMet Gln Gln Leu Pro Ala 50 55 60 tac caa gga gaa ggt cca tat tgc aac cgcacc tgg gat gga tgg ctg 240 Tyr Gln Gly Glu Gly Pro Tyr Cys Asn Arg ThrTrp Asp Gly Trp Leu 65 70 75 80 tgc tgg gat gac aca ccg gct gga gta ttgtcc tat cag ttc tgc cca 288 Cys Trp Asp Asp Thr Pro Ala Gly Val Leu SerTyr Gln Phe Cys Pro 85 90 95 gat tat ttt ccg gat ttt gat cca tca gaa aaggtt aca aaa tac tgt 336 Asp Tyr Phe Pro Asp Phe Asp Pro Ser Glu Lys ValThr Lys Tyr Cys 100 105 110 gat gaa aaa ggt gtt tgg ttt aaa cat cct gaaaac aat cga acc tgg 384 Asp Glu Lys Gly Val Trp Phe Lys His Pro Glu AsnAsn Arg Thr Trp 115 120 125 tcc aac tat act atg tgc aat gct ttc act cctgag aaa ctg aag aat 432 Ser Asn Tyr Thr Met Cys Asn Ala Phe Thr Pro GluLys Leu Lys Asn 130 135 140 gca tat gtt ctg tac tat ttg gct att gtg ggtcat tct ttg tca att 480 Ala Tyr Val Leu Tyr Tyr Leu Ala Ile Val Gly HisSer Leu Ser Ile 145 150 155 160 ttc acc cta gtg att tcc ctg ggg att ttcgtg ttt ttc agg agc ctt 528 Phe Thr Leu Val Ile Ser Leu Gly Ile Phe ValPhe Phe Arg Ser Leu 165 170 175 ggc tgc caa agg gta acc ctg cac aag aacatg ttt ctt act tac att 576 Gly Cys Gln Arg Val Thr Leu His Lys Asn MetPhe Leu Thr Tyr Ile 180 185 190 ctg aat tct atg att atc atc atc cac ctggtt gaa gta gta ccc aat 624 Leu Asn Ser Met Ile Ile Ile Ile His Leu ValGlu Val Val Pro Asn 195 200 205 gga gag ctc gtg cga agg gac ccg gtg agctgc aag att ttg cat ttt 672 Gly Glu Leu Val Arg Arg Asp Pro Val Ser CysLys Ile Leu His Phe 210 215 220 ttc cac cag tac atg atg gcc tgc aac tatttc tgg atg ctc tgt gaa 720 Phe His Gln Tyr Met Met Ala Cys Asn Tyr PheTrp Met Leu Cys Glu 225 230 235 240 ggg atc tat ctt cat aca ctc att gtcgtg gct gtg ttt act gag aag 768 Gly Ile Tyr Leu His Thr Leu Ile Val ValAla Val Phe Thr Glu Lys 245 250 255 caa cgc ttg cgg tgg tat tat ctc ttgggc tgg ggg ttc ccg ctg gtg 816 Gln Arg Leu Arg Trp Tyr Tyr Leu Leu GlyTrp Gly Phe Pro Leu Val 260 265 270 cca acc act atc cat gct att acc agggcc gtg tac ttc aat gac aac 864 Pro Thr Thr Ile His Ala Ile Thr Arg AlaVal Tyr Phe Asn Asp Asn 275 280 285 tgc tgg ctg agt gtg gaa acc cat ttgctt tac ata atc cat gga cct 912 Cys Trp Leu Ser Val Glu Thr His Leu LeuTyr Ile Ile His Gly Pro 290 295 300 gtc atg gcg gca ctt gtg gtc aat ttcttc ttt ttg ctc aac att gtc 960 Val Met Ala Ala Leu Val Val Asn Phe PhePhe Leu Leu Asn Ile Val 305 310 315 320 cgg gtg ctt gtg acc aaa atg agggaa acc cat gag gcg gaa tcc cac 1008 Arg Val Leu Val Thr Lys Met Arg GluThr His Glu Ala Glu Ser His 325 330 335 atg tac ctg aag gct gtg aag gccacc atg atc ctt gtg ccc ctg ctg 1056 Met Tyr Leu Lys Ala Val Lys Ala ThrMet Ile Leu Val Pro Leu Leu 340 345 350 gga atc cag ttt gtc gtc ttt ccctgg aga cct tcc aac aag atg ctt 1104 Gly Ile Gln Phe Val Val Phe Pro TrpArg Pro Ser Asn Lys Met Leu 355 360 365 ggg aag ata tat gat tac gtg atgcac tct ctg att cat ttc cag ggc 1152 Gly Lys Ile Tyr Asp Tyr Val Met HisSer Leu Ile His Phe Gln Gly 370 375 380 ttc ttt gtt gcg acc atc tac tgcttc tgc aac aat gag gtc caa acc 1200 Phe Phe Val Ala Thr Ile Tyr Cys PheCys Asn Asn Glu Val Gln Thr 385 390 395 400 acc gtg aag cgc caa tgg gcccaa ttc aaa att cag tgg aac cag cgt 1248 Thr Val Lys Arg Gln Trp Ala GlnPhe Lys Ile Gln Trp Asn Gln Arg 405 410 415 tgg ggg agg cgc ccc tcc aaccgc tct gct cgc gct gca gcc gct gct 1296 Trp Gly Arg Arg Pro Ser Asn ArgSer Ala Arg Ala Ala Ala Ala Ala 420 425 430 gcg gag gct ggc gac atc ccaatt tac atc tgc cat cag gag ctg agg 1344 Ala Glu Ala Gly Asp Ile Pro IleTyr Ile Cys His Gln Glu Leu Arg 435 440 445 aat gaa cca gcc aac aac caaggc gag gag agt gct gag atc atc cct 1392 Asn Glu Pro Ala Asn Asn Gln GlyGlu Glu Ser Ala Glu Ile Ile Pro 450 455 460 ttg aat atc ata gag caa gagtca tct gct tga 1425 Leu Asn Ile Ile Glu Gln Glu Ser Ser Ala 465 470 6474 PRT Homo sapiens 6 Met Arg Phe Thr Phe Thr Ser Arg Cys Leu Ala LeuPhe Leu Leu Leu 1 5 10 15 Asn His Pro Thr Pro Ile Leu Pro Ala Phe SerAsn Gln Thr Tyr Pro 20 25 30 Thr Ile Glu Pro Lys Pro Phe Leu Tyr Val ValGly Arg Lys Lys Met 35 40 45 Met Asp Ala Gln Tyr Lys Cys Tyr Asp Arg MetGln Gln Leu Pro Ala 50 55 60 Tyr Gln Gly Glu Gly Pro Tyr Cys Asn Arg ThrTrp Asp Gly Trp Leu 65 70 75 80 Cys Trp Asp Asp Thr Pro Ala Gly Val LeuSer Tyr Gln Phe Cys Pro 85 90 95 Asp Tyr Phe Pro Asp Phe Asp Pro Ser GluLys Val Thr Lys Tyr Cys 100 105 110 Asp Glu Lys Gly Val Trp Phe Lys HisPro Glu Asn Asn Arg Thr Trp 115 120 125 Ser Asn Tyr Thr Met Cys Asn AlaPhe Thr Pro Glu Lys Leu Lys Asn 130 135 140 Ala Tyr Val Leu Tyr Tyr LeuAla Ile Val Gly His Ser Leu Ser Ile 145 150 155 160 Phe Thr Leu Val IleSer Leu Gly Ile Phe Val Phe Phe Arg Ser Leu 165 170 175 Gly Cys Gln ArgVal Thr Leu His Lys Asn Met Phe Leu Thr Tyr Ile 180 185 190 Leu Asn SerMet Ile Ile Ile Ile His Leu Val Glu Val Val Pro Asn 195 200 205 Gly GluLeu Val Arg Arg Asp Pro Val Ser Cys Lys Ile Leu His Phe 210 215 220 PheHis Gln Tyr Met Met Ala Cys Asn Tyr Phe Trp Met Leu Cys Glu 225 230 235240 Gly Ile Tyr Leu His Thr Leu Ile Val Val Ala Val Phe Thr Glu Lys 245250 255 Gln Arg Leu Arg Trp Tyr Tyr Leu Leu Gly Trp Gly Phe Pro Leu Val260 265 270 Pro Thr Thr Ile His Ala Ile Thr Arg Ala Val Tyr Phe Asn AspAsn 275 280 285 Cys Trp Leu Ser Val Glu Thr His Leu Leu Tyr Ile Ile HisGly Pro 290 295 300 Val Met Ala Ala Leu Val Val Asn Phe Phe Phe Leu LeuAsn Ile Val 305 310 315 320 Arg Val Leu Val Thr Lys Met Arg Glu Thr HisGlu Ala Glu Ser His 325 330 335 Met Tyr Leu Lys Ala Val Lys Ala Thr MetIle Leu Val Pro Leu Leu 340 345 350 Gly Ile Gln Phe Val Val Phe Pro TrpArg Pro Ser Asn Lys Met Leu 355 360 365 Gly Lys Ile Tyr Asp Tyr Val MetHis Ser Leu Ile His Phe Gln Gly 370 375 380 Phe Phe Val Ala Thr Ile TyrCys Phe Cys Asn Asn Glu Val Gln Thr 385 390 395 400 Thr Val Lys Arg GlnTrp Ala Gln Phe Lys Ile Gln Trp Asn Gln Arg 405 410 415 Trp Gly Arg ArgPro Ser Asn Arg Ser Ala Arg Ala Ala Ala Ala Ala 420 425 430 Ala Glu AlaGly Asp Ile Pro Ile Tyr Ile Cys His Gln Glu Leu Arg 435 440 445 Asn GluPro Ala Asn Asn Gln Gly Glu Glu Ser Ala Glu Ile Ile Pro 450 455 460 LeuAsn Ile Ile Glu Gln Glu Ser Ser Ala 465 470 7 1339 DNA Homo sapiens CDS(23)..(1306) 7 ccaaaaatga ggacgaaaga ag atg atg gat gca cag tac aaa tgctat gac 52 Met Met Asp Ala Gln Tyr Lys Cys Tyr Asp 1 5 10 cga atg cagcag tta ccc gca tat caa gga gaa ggt cca tat tgc aat 100 Arg Met Gln GlnLeu Pro Ala Tyr Gln Gly Glu Gly Pro Tyr Cys Asn 15 20 25 cgc acc tgg gatgga tgg ctg tgc tgg gat gac aca ccg gct gga gta 148 Arg Thr Trp Asp GlyTrp Leu Cys Trp Asp Asp Thr Pro Ala Gly Val 30 35 40 ttg tcc tat cag ttctgc cca gat tat ttt ccg gat ttt gat cca tca 196 Leu Ser Tyr Gln Phe CysPro Asp Tyr Phe Pro Asp Phe Asp Pro Ser 45 50 55 gaa aag gtt aca aaa tactgt gat gaa aaa ggt gtt tgg ttt aaa cat 244 Glu Lys Val Thr Lys Tyr CysAsp Glu Lys Gly Val Trp Phe Lys His 60 65 70 cct gaa aac aat cga acc tggtcc aac tat act atg tgc aat gct ttc 292 Pro Glu Asn Asn Arg Thr Trp SerAsn Tyr Thr Met Cys Asn Ala Phe 75 80 85 90 act cct gag aaa ctg aag aatgca tat gtt ctg tac tat ttg gct att 340 Thr Pro Glu Lys Leu Lys Asn AlaTyr Val Leu Tyr Tyr Leu Ala Ile 95 100 105 gtg ggt cat tct ttg tca attttc acc cta gtg att tcc ctg ggg att 388 Val Gly His Ser Leu Ser Ile PheThr Leu Val Ile Ser Leu Gly Ile 110 115 120 ttc gtg ttt ttc agg agc cttggc tgc caa agg gta acc ctg cac aag 436 Phe Val Phe Phe Arg Ser Leu GlyCys Gln Arg Val Thr Leu His Lys 125 130 135 aac atg ttt ctt act tac attctg aat tct atg att atc atc atc cac 484 Asn Met Phe Leu Thr Tyr Ile LeuAsn Ser Met Ile Ile Ile Ile His 140 145 150 ctg gtt gaa gta gta ccc aatgga gag ctc gtg cga agg gac ccg gtg 532 Leu Val Glu Val Val Pro Asn GlyGlu Leu Val Arg Arg Asp Pro Val 155 160 165 170 agc tgc aag att ttg catttt ttc cac cag tac atg atg gcc tgc aac 580 Ser Cys Lys Ile Leu His PhePhe His Gln Tyr Met Met Ala Cys Asn 175 180 185 tat ttc tgg atg ctc tgtgaa ggg atc tat ctt cat aca ctc att gtc 628 Tyr Phe Trp Met Leu Cys GluGly Ile Tyr Leu His Thr Leu Ile Val 190 195 200 gtg gct gtg ttt act gagaag caa cgc ttg cgg tgg tat tat ctc ttg 676 Val Ala Val Phe Thr Glu LysGln Arg Leu Arg Trp Tyr Tyr Leu Leu 205 210 215 ggc tgg ggg ttc ccg ctggtg cca acc act atc cat gct att acc agg 724 Gly Trp Gly Phe Pro Leu ValPro Thr Thr Ile His Ala Ile Thr Arg 220 225 230 gcc gtg tac ttc aat gacaac tgc tgg ctg agt gtg gaa acc cat ttg 772 Ala Val Tyr Phe Asn Asp AsnCys Trp Leu Ser Val Glu Thr His Leu 235 240 245 250 ctt tac ata atc catgga cct gtc atg gcg gca ctt gtg gtc aat ttc 820 Leu Tyr Ile Ile His GlyPro Val Met Ala Ala Leu Val Val Asn Phe 255 260 265 ttc ttt ttg ctc aacatt gtc cgg gtg ctt gtg acc aaa atg agg gaa 868 Phe Phe Leu Leu Asn IleVal Arg Val Leu Val Thr Lys Met Arg Glu 270 275 280 acc cat gag gcg gaatcc cac atg tac ctg aag gct gtg aag gcc acc 916 Thr His Glu Ala Glu SerHis Met Tyr Leu Lys Ala Val Lys Ala Thr 285 290 295 atg acc ctt gtg cccctg ctg gga atc cag ttt gtc gtc ttt ccc tgg 964 Met Thr Leu Val Pro LeuLeu Gly Ile Gln Phe Val Val Phe Pro Trp 300 305 310 aga cct tcc aac aagatg ctt ggg aag ata tat gat tac gtg atg cac 1012 Arg Pro Ser Asn Lys MetLeu Gly Lys Ile Tyr Asp Tyr Val Met His 315 320 325 330 tct ctg att catttc cag ggc ttc ttt gtt gcg acc atc tac tgc ttc 1060 Ser Leu Ile His PheGln Gly Phe Phe Val Ala Thr Ile Tyr Cys Phe 335 340 345 tgc aac aat gaggtc caa acc acc gtg aag cgc caa tgg gcc caa ttc 1108 Cys Asn Asn Glu ValGln Thr Thr Val Lys Arg Gln Trp Ala Gln Phe 350 355 360 aaa att cag tggaac cag cgt tgg ggg agg cgc ccc tcc aac cgc tct 1156 Lys Ile Gln Trp AsnGln Arg Trp Gly Arg Arg Pro Ser Asn Arg Ser 365 370 375 gct cgc gct gcagcc gct gct gcg gag gct ggc gac atc cca att tac 1204 Ala Arg Ala Ala AlaAla Ala Ala Glu Ala Gly Asp Ile Pro Ile Tyr 380 385 390 atc tgc cat caggag ctg agg aat gaa cca gcc aac aac caa ggc gag 1252 Ile Cys His Gln GluLeu Arg Asn Glu Pro Ala Asn Asn Gln Gly Glu 395 400 405 410 gag agt gctgag atc atc cct ttg aat atc ata gag caa gag tca tct 1300 Glu Ser Ala GluIle Ile Pro Leu Asn Ile Ile Glu Gln Glu Ser Ser 415 420 425 gct tgaatgtgaagca aacacagtat cgtgatcact gag 1339 Ala 8 427 PRT Homo sapiens 8Met Met Asp Ala Gln Tyr Lys Cys Tyr Asp Arg Met Gln Gln Leu Pro 1 5 1015 Ala Tyr Gln Gly Glu Gly Pro Tyr Cys Asn Arg Thr Trp Asp Gly Trp 20 2530 Leu Cys Trp Asp Asp Thr Pro Ala Gly Val Leu Ser Tyr Gln Phe Cys 35 4045 Pro Asp Tyr Phe Pro Asp Phe Asp Pro Ser Glu Lys Val Thr Lys Tyr 50 5560 Cys Asp Glu Lys Gly Val Trp Phe Lys His Pro Glu Asn Asn Arg Thr 65 7075 80 Trp Ser Asn Tyr Thr Met Cys Asn Ala Phe Thr Pro Glu Lys Leu Lys 8590 95 Asn Ala Tyr Val Leu Tyr Tyr Leu Ala Ile Val Gly His Ser Leu Ser100 105 110 Ile Phe Thr Leu Val Ile Ser Leu Gly Ile Phe Val Phe Phe ArgSer 115 120 125 Leu Gly Cys Gln Arg Val Thr Leu His Lys Asn Met Phe LeuThr Tyr 130 135 140 Ile Leu Asn Ser Met Ile Ile Ile Ile His Leu Val GluVal Val Pro 145 150 155 160 Asn Gly Glu Leu Val Arg Arg Asp Pro Val SerCys Lys Ile Leu His 165 170 175 Phe Phe His Gln Tyr Met Met Ala Cys AsnTyr Phe Trp Met Leu Cys 180 185 190 Glu Gly Ile Tyr Leu His Thr Leu IleVal Val Ala Val Phe Thr Glu 195 200 205 Lys Gln Arg Leu Arg Trp Tyr TyrLeu Leu Gly Trp Gly Phe Pro Leu 210 215 220 Val Pro Thr Thr Ile His AlaIle Thr Arg Ala Val Tyr Phe Asn Asp 225 230 235 240 Asn Cys Trp Leu SerVal Glu Thr His Leu Leu Tyr Ile Ile His Gly 245 250 255 Pro Val Met AlaAla Leu Val Val Asn Phe Phe Phe Leu Leu Asn Ile 260 265 270 Val Arg ValLeu Val Thr Lys Met Arg Glu Thr His Glu Ala Glu Ser 275 280 285 His MetTyr Leu Lys Ala Val Lys Ala Thr Met Thr Leu Val Pro Leu 290 295 300 LeuGly Ile Gln Phe Val Val Phe Pro Trp Arg Pro Ser Asn Lys Met 305 310 315320 Leu Gly Lys Ile Tyr Asp Tyr Val Met His Ser Leu Ile His Phe Gln 325330 335 Gly Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn Asn Glu Val Gln340 345 350 Thr Thr Val Lys Arg Gln Trp Ala Gln Phe Lys Ile Gln Trp AsnGln 355 360 365 Arg Trp Gly Arg Arg Pro Ser Asn Arg Ser Ala Arg Ala AlaAla Ala 370 375 380 Ala Ala Glu Ala Gly Asp Ile Pro Ile Tyr Ile Cys HisGln Glu Leu 385 390 395 400 Arg Asn Glu Pro Ala Asn Asn Gln Gly Glu GluSer Ala Glu Ile Ile 405 410 415 Pro Leu Asn Ile Ile Glu Gln Glu Ser SerAla 420 425 9 3588 DNA Homo sapiens CDS (248)..(1720) 9 gtgcgcacgtccgcacctca ccctgcggct gacatctcct gcccaggaga tgggcgctga 60 agcttgagcgcctgagtccc tggagccaca cctgcgaaca ccctttgctt ctattgagct 120 gtgcccagccgcccagtgac agaattccag aataaatgat tcccactgat ccacccactt 180 ttgccaccccaggatgcaat tttctggaga gaagattagt ggacaaagag atcttcaaaa 240 atcaaaa atgagg ttc aca ttt aca agc cgg tgc ttg gca ctg ttt ctt 289 Met Arg Phe ThrPhe Thr Ser Arg Cys Leu Ala Leu Phe Leu 1 5 10 ctt cta aat cac cca acccca att ctt cct gcc ttt tca aat caa acc 337 Leu Leu Asn His Pro Thr ProIle Leu Pro Ala Phe Ser Asn Gln Thr 15 20 25 30 tat cca aca ata gag cccaag cca ttt ctt tac gtc gta gga cga aag 385 Tyr Pro Thr Ile Glu Pro LysPro Phe Leu Tyr Val Val Gly Arg Lys 35 40 45 aag atg atg gat gca cag tacaaa tgc tat gac cga atg cag cag tta 433 Lys Met Met Asp Ala Gln Tyr LysCys Tyr Asp Arg Met Gln Gln Leu 50 55 60 ccc gca tac caa gga gaa ggt ccatat tgc aat cgc acc tgg gat gga 481 Pro Ala Tyr Gln Gly Glu Gly Pro TyrCys Asn Arg Thr Trp Asp Gly 65 70 75 tgg ctg tgc tgg gat gac aca ccg gctgga gta ttg tcc tat cag ttc 529 Trp Leu Cys Trp Asp Asp Thr Pro Ala GlyVal Leu Ser Tyr Gln Phe 80 85 90 tgc cca gat tat ttt ccg gat ttt gat ccatca gaa aag gtt aca aaa 577 Cys Pro Asp Tyr Phe Pro Asp Phe Asp Pro SerGlu Lys Val Thr Lys 95 100 105 110 tac tgt gat gaa aaa ggt gtt tgg tttaaa cat cct gaa aac aat cga 625 Tyr Cys Asp Glu Lys Gly Val Trp Phe LysHis Pro Glu Asn Asn Arg 115 120 125 acc tgg tcc aac tat act atg tgc aatgct ttc act cct gag aaa ctg 673 Thr Trp Ser Asn Tyr Thr Met Cys Asn AlaPhe Thr Pro Glu Lys Leu 130 135 140 aag aat gca tat gtt ctg tac tat ttggct att gtg ggt cat tct ttg 721 Lys Asn Ala Tyr Val Leu Tyr Tyr Leu AlaIle Val Gly His Ser Leu 145 150 155 tca att ttc acc cta gtg att tcc ctgggg att ttc gtg ttt ttc aga 769 Ser Ile Phe Thr Leu Val Ile Ser Leu GlyIle Phe Val Phe Phe Arg 160 165 170 aaa ttg aca act att ttt cct ttg aattgg aaa tat agg aag gca ttg 817 Lys Leu Thr Thr Ile Phe Pro Leu Asn TrpLys Tyr Arg Lys Ala Leu 175 180 185 190 agc ctt ggc tgc caa agg gta accctg cac aag aac atg ttt ctt act 865 Ser Leu Gly Cys Gln Arg Val Thr LeuHis Lys Asn Met Phe Leu Thr 195 200 205 tac att ctg aat tct atg att atcatc atc cac ctg gtt gaa gta gta 913 Tyr Ile Leu Asn Ser Met Ile Ile IleIle His Leu Val Glu Val Val 210 215 220 ccc aat gga gag ctc gtg cga agggac ccg gtg agc tgc aag att ttg 961 Pro Asn Gly Glu Leu Val Arg Arg AspPro Val Ser Cys Lys Ile Leu 225 230 235 cat ttt ttc cac cag tac atg atggcc tgc aac tat ttc tgg atg ctc 1009 His Phe Phe His Gln Tyr Met Met AlaCys Asn Tyr Phe Trp Met Leu 240 245 250 tgt gaa ggg atc tat ctt cat acactc att gtc gtg gct gtg ttt act 1057 Cys Glu Gly Ile Tyr Leu His Thr LeuIle Val Val Ala Val Phe Thr 255 260 265 270 gag aag caa cgc ttg cgg tggtat tat ctc ttg ggc tgg ggg ttc ccg 1105 Glu Lys Gln Arg Leu Arg Trp TyrTyr Leu Leu Gly Trp Gly Phe Pro 275 280 285 ctg gtg cca acc act atc catgct att acc agg gcc gtg tac ttc aat 1153 Leu Val Pro Thr Thr Ile His AlaIle Thr Arg Ala Val Tyr Phe Asn 290 295 300 gac aac tgc tgg ctg agt gtggaa acc cat ttg ctt tac ata atc cat 1201 Asp Asn Cys Trp Leu Ser Val GluThr His Leu Leu Tyr Ile Ile His 305 310 315 gga cct gtc atg gcg gca cttgtg gtc aat ttc ttc ttt ttg ctc aac 1249 Gly Pro Val Met Ala Ala Leu ValVal Asn Phe Phe Phe Leu Leu Asn 320 325 330 att gtc cgg gtg ctt gtg accaaa atg agg gaa acc cat gag gcg gaa 1297 Ile Val Arg Val Leu Val Thr LysMet Arg Glu Thr His Glu Ala Glu 335 340 345 350 tcc cac atg tac ctg aaggct gtg aag gcc acc atg atc ctt gtg ccc 1345 Ser His Met Tyr Leu Lys AlaVal Lys Ala Thr Met Ile Leu Val Pro 355 360 365 ctg ctg gga atc cag tttgtc gtc ttt ccc tgg aga cct tcc aac aag 1393 Leu Leu Gly Ile Gln Phe ValVal Phe Pro Trp Arg Pro Ser Asn Lys 370 375 380 atg ctt ggg aag ata tatgat tac gtg atg cac tct ctg att cat ttc 1441 Met Leu Gly Lys Ile Tyr AspTyr Val Met His Ser Leu Ile His Phe 385 390 395 cag ggc ttc ttt gtt gcgacc atc tac tgc ttc tgc aac aat gag gtc 1489 Gln Gly Phe Phe Val Ala ThrIle Tyr Cys Phe Cys Asn Asn Glu Val 400 405 410 caa acc acc gtg aag cgccaa tgg gcc caa ttc aaa att cag tgg aac 1537 Gln Thr Thr Val Lys Arg GlnTrp Ala Gln Phe Lys Ile Gln Trp Asn 415 420 425 430 cag cgt tgg ggg aggcgc ccc tcc aac cgc tct gct cgc gct gca gcc 1585 Gln Arg Trp Gly Arg ArgPro Ser Asn Arg Ser Ala Arg Ala Ala Ala 435 440 445 gct gct gcg gag gctggc gac atc cca att tac atc tgc cat cag gag 1633 Ala Ala Ala Glu Ala GlyAsp Ile Pro Ile Tyr Ile Cys His Gln Glu 450 455 460 ccg agg aat gaa ccagcc aac aac caa ggc gag gag agt gct gag atc 1681 Pro Arg Asn Glu Pro AlaAsn Asn Gln Gly Glu Glu Ser Ala Glu Ile 465 470 475 atc cct ttg aat atcata gag caa gag tca tct gct tga atgtgaagca 1730 Ile Pro Leu Asn Ile IleGlu Gln Glu Ser Ser Ala 480 485 490 aacacagtat cgtgatcact gagccatcatttcctgggag aaagaccatg catttaaagt 1790 attctccatc ctcccaggaa ccgaacatatcatttgtgaa gaattattca gtgaatttgt 1850 ccattgtaaa tctgaagaaa gttattcttggtactgttgc tttgggagac agtctaggaa 1910 tggagtctcc cactgcaact tgtgaactccatcattcatc caggactgag atgcaaatgt 1970 cacagtaatg caagcaaagt atcaaagaaaaacaatgaaa ttgacctagt tcagatacag 2030 ggtgctcctt gtcaatactg agccatttatacctttgaaa tattaaaatc actgtcaata 2090 tttttatttt taactctgga ttttgaattagattatttct gtatttggct atggatctga 2150 tttttaattt ttttaaattt cagtcaattctgatgttact gagatgtttt accatcctta 2210 caatgtaaac cacatgaact acgtgacctctgcaagacaa agcggctttc taatagagag 2270 attagtaaat atgtgaagaa aaagacctgcatttggcagg aagatgtatg ctttgaatgc 2330 aaaagaaatt tagagtcaat ttgctgaaaacattacatgc tcagcttggt tttggacaag 2390 cctgtccatt gggcaggacc tagctgttgtaaagaattgg tcttaatgtt gaatgtattt 2450 tggttgctga tgtttataaa ctgagaggtcacaaagaatc tatcactaaa aatttttaca 2510 aaactgccaa aaatataatt cttagtggaagacaatactc cctttaaaga aagagagttt 2570 gccactcccc taaactccag gatttataaagcaaattact ccaaggttta taaagcagat 2630 tacctcttgc ccttgggtgc tatctagcagtaaaagataa atttgttgaa tattggtaat 2690 taaaagactc cacataagtc cattaactgctttccaccca gcttcaaagc ttaaaaagag 2750 ctcaggcttt tccaggaaga tccaggagggctaattagaa atcaacttgt ggttgaccgc 2810 ttgtttcttg ttattaccaa aacaggaggggaaaaaatta actgctccaa atttaaccat 2870 aaatcaattc atgtttaacg tttctcattaaaatccagta ttatattatc atatctctct 2930 ttacttccca gtataagatt tttgaaaatcctgaataaac cagtatcgtt actggcacct 2990 gaaattaatt tgtgaatttg caacagtaatcagagttacc attatttaat ttgtatgcta 3050 aatgaggagg tacattgaaa ccctccaaatctccagtctc atctatgtca tattttgcca 3110 ctgcctttca gaagtgattt agttgtggaaagataataaa ttgatttgtt atggttacat 3170 attcagcgca cccagagaaa attaattatatttctacaga gaaaatgaat ttgggatact 3230 aaagtagttt aagtctcctt tactgaatgtaaggggggga tcgaaaagaa ggtatttttc 3290 caatcacagt gttatgtagt attgttctatttttgtttac aaacatggaa aacagagtat 3350 ttctggcagc tgtggtacaa atgtgataatatattgctaa aatattttag atgttattat 3410 gctaatatag taggggttga agaaaacaaaatagcttatt atagaattgc acatagttct 3470 gcccaaatta tgtgaaatgc ttatgcttgtgtatatgtat aaattaatac agagtacgtt 3530 aaaagcaaaa agatgtatat ttgcatatttttctaaagaa atatattatt catctttt 3588 10 490 PRT Homo sapiens 10 Met ArgPhe Thr Phe Thr Ser Arg Cys Leu Ala Leu Phe Leu Leu Leu 1 5 10 15 AsnHis Pro Thr Pro Ile Leu Pro Ala Phe Ser Asn Gln Thr Tyr Pro 20 25 30 ThrIle Glu Pro Lys Pro Phe Leu Tyr Val Val Gly Arg Lys Lys Met 35 40 45 MetAsp Ala Gln Tyr Lys Cys Tyr Asp Arg Met Gln Gln Leu Pro Ala 50 55 60 TyrGln Gly Glu Gly Pro Tyr Cys Asn Arg Thr Trp Asp Gly Trp Leu 65 70 75 80Cys Trp Asp Asp Thr Pro Ala Gly Val Leu Ser Tyr Gln Phe Cys Pro 85 90 95Asp Tyr Phe Pro Asp Phe Asp Pro Ser Glu Lys Val Thr Lys Tyr Cys 100 105110 Asp Glu Lys Gly Val Trp Phe Lys His Pro Glu Asn Asn Arg Thr Trp 115120 125 Ser Asn Tyr Thr Met Cys Asn Ala Phe Thr Pro Glu Lys Leu Lys Asn130 135 140 Ala Tyr Val Leu Tyr Tyr Leu Ala Ile Val Gly His Ser Leu SerIle 145 150 155 160 Phe Thr Leu Val Ile Ser Leu Gly Ile Phe Val Phe PheArg Lys Leu 165 170 175 Thr Thr Ile Phe Pro Leu Asn Trp Lys Tyr Arg LysAla Leu Ser Leu 180 185 190 Gly Cys Gln Arg Val Thr Leu His Lys Asn MetPhe Leu Thr Tyr Ile 195 200 205 Leu Asn Ser Met Ile Ile Ile Ile His LeuVal Glu Val Val Pro Asn 210 215 220 Gly Glu Leu Val Arg Arg Asp Pro ValSer Cys Lys Ile Leu His Phe 225 230 235 240 Phe His Gln Tyr Met Met AlaCys Asn Tyr Phe Trp Met Leu Cys Glu 245 250 255 Gly Ile Tyr Leu His ThrLeu Ile Val Val Ala Val Phe Thr Glu Lys 260 265 270 Gln Arg Leu Arg TrpTyr Tyr Leu Leu Gly Trp Gly Phe Pro Leu Val 275 280 285 Pro Thr Thr IleHis Ala Ile Thr Arg Ala Val Tyr Phe Asn Asp Asn 290 295 300 Cys Trp LeuSer Val Glu Thr His Leu Leu Tyr Ile Ile His Gly Pro 305 310 315 320 ValMet Ala Ala Leu Val Val Asn Phe Phe Phe Leu Leu Asn Ile Val 325 330 335Arg Val Leu Val Thr Lys Met Arg Glu Thr His Glu Ala Glu Ser His 340 345350 Met Tyr Leu Lys Ala Val Lys Ala Thr Met Ile Leu Val Pro Leu Leu 355360 365 Gly Ile Gln Phe Val Val Phe Pro Trp Arg Pro Ser Asn Lys Met Leu370 375 380 Gly Lys Ile Tyr Asp Tyr Val Met His Ser Leu Ile His Phe GlnGly 385 390 395 400 Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn Asn GluVal Gln Thr 405 410 415 Thr Val Lys Arg Gln Trp Ala Gln Phe Lys Ile GlnTrp Asn Gln Arg 420 425 430 Trp Gly Arg Arg Pro Ser Asn Arg Ser Ala ArgAla Ala Ala Ala Ala 435 440 445 Ala Glu Ala Gly Asp Ile Pro Ile Tyr IleCys His Gln Glu Pro Arg 450 455 460 Asn Glu Pro Ala Asn Asn Gln Gly GluGlu Ser Ala Glu Ile Ile Pro 465 470 475 480 Leu Asn Ile Ile Glu Gln GluSer Ser Ala 485 490 11 3588 DNA Homo sapiens CDS (248)..(1720) 11gtgcgcacgt ccgcacctca ccctgcggct gacatctcct gcccaggaga tgggcgctga 60agcttgagcg cctgagtccc tggagccaca cctgcgaaca ccctttgctt ctattgagct 120gtgcccagcc gcccagtgac agaattccag aataaatgat tcccactgat ccacccactt 180ttgccacccc aggatgcaat tttctggaga gaagattagt ggacaaagag atcttcaaaa 240atcaaaa atg agg ttc aca ttt aca agc cgg tgc ttg gca ctg ttt ctt 289 MetArg Phe Thr Phe Thr Ser Arg Cys Leu Ala Leu Phe Leu 1 5 10 ctt cta aatcac cca acc cca att ctt cct gcc ttt tca aat caa acc 337 Leu Leu Asn HisPro Thr Pro Ile Leu Pro Ala Phe Ser Asn Gln Thr 15 20 25 30 tat cca acaata gag ccc aag cca ttt ctt tac gtc gta gga cga aag 385 Tyr Pro Thr IleGlu Pro Lys Pro Phe Leu Tyr Val Val Gly Arg Lys 35 40 45 aag atg atg gatgca cag tac aaa tgc tat gac cga atg cag cag tta 433 Lys Met Met Asp AlaGln Tyr Lys Cys Tyr Asp Arg Met Gln Gln Leu 50 55 60 ccc gca tac caa ggagaa ggt cca tat tgc aat cgc acc tgg gat gga 481 Pro Ala Tyr Gln Gly GluGly Pro Tyr Cys Asn Arg Thr Trp Asp Gly 65 70 75 tgg ctg tgc tgg gat gacaca ccg gct gga gta ttg tcc tat cag ttc 529 Trp Leu Cys Trp Asp Asp ThrPro Ala Gly Val Leu Ser Tyr Gln Phe 80 85 90 tgc cca gat tat ttt ccg gatttt gat cca tca gaa aag gtt aca aaa 577 Cys Pro Asp Tyr Phe Pro Asp PheAsp Pro Ser Glu Lys Val Thr Lys 95 100 105 110 tac tgt gat gaa aaa ggtgtt tgg ttt aaa cat cct gaa aac aat cga 625 Tyr Cys Asp Glu Lys Gly ValTrp Phe Lys His Pro Glu Asn Asn Arg 115 120 125 acc tgg tcc aac tat actatg tgc aat gct ttc act cct gag aaa ctg 673 Thr Trp Ser Asn Tyr Thr MetCys Asn Ala Phe Thr Pro Glu Lys Leu 130 135 140 aag aat gca tat gtt ctgtac tat ttg gct att gtg ggt cat tct ttg 721 Lys Asn Ala Tyr Val Leu TyrTyr Leu Ala Ile Val Gly His Ser Leu 145 150 155 tca att ttc acc cta gtgatt ttc ctg ggg att ttc gtg ttt ttc aga 769 Ser Ile Phe Thr Leu Val IlePhe Leu Gly Ile Phe Val Phe Phe Arg 160 165 170 aaa ttg aca act att tttcct ttg aat tgg aaa tat agg aag gca ttg 817 Lys Leu Thr Thr Ile Phe ProLeu Asn Trp Lys Tyr Arg Lys Ala Leu 175 180 185 190 agc ctt ggc tgc caaagg gta acc ctg cac aag aac atg ttt ctt act 865 Ser Leu Gly Cys Gln ArgVal Thr Leu His Lys Asn Met Phe Leu Thr 195 200 205 tac att ctg aat tctatg att atc atc atc cac ctg gtt gaa gta gta 913 Tyr Ile Leu Asn Ser MetIle Ile Ile Ile His Leu Val Glu Val Val 210 215 220 ccc aat gga gag ctcgtg cga agg gac ccg gtg agc tgc aag att ttg 961 Pro Asn Gly Glu Leu ValArg Arg Asp Pro Val Ser Cys Lys Ile Leu 225 230 235 cat ttt ttc cac cagtac atg atg gcc tgc aac tat ttc tgg atg ctc 1009 His Phe Phe His Gln TyrMet Met Ala Cys Asn Tyr Phe Trp Met Leu 240 245 250 tgt gaa ggg atc tatctt cat aca ctc att gtc gtg gct gtg ttt act 1057 Cys Glu Gly Ile Tyr LeuHis Thr Leu Ile Val Val Ala Val Phe Thr 255 260 265 270 gag aag caa cgcttg cgg tgg tat tat ctc ttg ggc tgg ggg ttc ccg 1105 Glu Lys Gln Arg LeuArg Trp Tyr Tyr Leu Leu Gly Trp Gly Phe Pro 275 280 285 ctg gtg cca accact atc cat gct att acc agg gcc gtg tac ttc aat 1153 Leu Val Pro Thr ThrIle His Ala Ile Thr Arg Ala Val Tyr Phe Asn 290 295 300 gac aac tgc tggctg agt gtg gaa acc cat ttg ctt tac ata atc cat 1201 Asp Asn Cys Trp LeuSer Val Glu Thr His Leu Leu Tyr Ile Ile His 305 310 315 gga cct gtc atggcg gca ctt gtg gtc aat ttc ttc ttt ttg ctc aac 1249 Gly Pro Val Met AlaAla Leu Val Val Asn Phe Phe Phe Leu Leu Asn 320 325 330 att gtc cgg gtgctt gtg acc aaa atg agg gaa acc cat gag gcg gaa 1297 Ile Val Arg Val LeuVal Thr Lys Met Arg Glu Thr His Glu Ala Glu 335 340 345 350 tcc cac atgtac ctg aag gct gtg aag gcc acc atg atc ctt gtg ccc 1345 Ser His Met TyrLeu Lys Ala Val Lys Ala Thr Met Ile Leu Val Pro 355 360 365 ctg ctg ggaatc cag ttt gtc gtc ttt ccc tgg aga cct tcc aac aag 1393 Leu Leu Gly IleGln Phe Val Val Phe Pro Trp Arg Pro Ser Asn Lys 370 375 380 atg ctt gggaag ata tat gat tac gtg atg cac tct ctg att cat ttc 1441 Met Leu Gly LysIle Tyr Asp Tyr Val Met His Ser Leu Ile His Phe 385 390 395 cag ggc ttcttt gtt gcg acc atc tac tgc ttc tgc aac aat gag gtc 1489 Gln Gly Phe PheVal Ala Thr Ile Tyr Cys Phe Cys Asn Asn Glu Val 400 405 410 caa acc accgtg aag cgc caa tgg gcc caa ttc aaa att cag tgg aac 1537 Gln Thr Thr ValLys Arg Gln Trp Ala Gln Phe Lys Ile Gln Trp Asn 415 420 425 430 cag cgttgg ggg agg cgc ccc tcc aac cgc tct gct cgc gct gca gcc 1585 Gln Arg TrpGly Arg Arg Pro Ser Asn Arg Ser Ala Arg Ala Ala Ala 435 440 445 gct gctgcg gag gct ggc gac atc cca att tac atc tgc cat cag gag 1633 Ala Ala AlaGlu Ala Gly Asp Ile Pro Ile Tyr Ile Cys His Gln Glu 450 455 460 ccg aggaat gaa cca gcc aac aac caa ggc gag gag agt gct gag atc 1681 Pro Arg AsnGlu Pro Ala Asn Asn Gln Gly Glu Glu Ser Ala Glu Ile 465 470 475 atc cctttg aat atc ata gag caa gag tca tct gct tga atgtgaagca 1730 Ile Pro LeuAsn Ile Ile Glu Gln Glu Ser Ser Ala 480 485 490 aacacagtat cgtgatcactgagccatcat ttcctgggag aaagaccatg catttaaagt 1790 attctccatc ctcccaggaaccgaacatat catttgtgaa gaattattca gtgaatttgt 1850 ccattgtaaa tctgaagaaagttattcttg gtactgttgc tttgggagac agtctaggaa 1910 tggagtctcc cactgcaacttgtgaactcc atcattcatc caggactgag atgcaaatgt 1970 cacagtaatg caagcaaagtatcaaagaaa aacaatgaaa ttgacctagt tcagatacag 2030 ggtgctcctt gtcaatactgagccatttat acctttgaaa tattaaaatc actgtcaata 2090 tttttatttt taactctggattttgaatta gattatttct gtatttggct atggatctga 2150 tttttaattt ttttaaatttcagtcaattc tgatgttact gagatgtttt accatcctta 2210 caatgtaaac cacatgaactacgtgacctc tgcaagacaa agcggctttc taatagagag 2270 attagtaaat atgtgaagaaaaagacctgc atttggcagg aagatgtatg ctttgaatgc 2330 aaaagaaatt tagagtcaatttgctgaaaa cattacatgc tcagcttggt tttggacaag 2390 cctgtccatt gggcaggacctagctgttgt aaagaattgg tcttaatgtt gaatgtattt 2450 tggttgctga tgtttataaactgagaggtc acaaagaatc tatcactaaa aatttttaca 2510 aaactgccaa aaatataattcttagtggaa gacaatactc cctttaaaga aagagagttt 2570 gccactcccc taaactccaggatttataaa gcaaattact ccaaggttta taaagcagat 2630 tacctcttgc ccttgggtgctatctagcag taaaagataa atttgttgaa tattggtaat 2690 taaaagactc cacataagtccattaactgc tttccaccca gcttcaaagc ttaaaaagag 2750 ctcaggcttt tccaggaagatccaggacgg ctaattagaa atcaacttgt ggttgaccgc 2810 ttgtttcttg ttattaccaaaacaggaggg gaaaaaatta actgctccaa atttaaccat 2870 aaatcaattc atgtttaacgtttctcatta aaatccagta ttatattatc atatctctct 2930 ttacttccca gtataagatttttgaaaatc ctgaataaac cagtatcgtt actggcacct 2990 gaaattaatt tgtgaatttgcaacagtaat cagagttacc attatttaat ttgtatgcta 3050 aatgaggagg tacattgaaaccctccaaat ctccagtctc atctatgtca tattttgcca 3110 ctgcctttca gaagtgatttagttgtggaa agataataaa ttgatttgtt atggttacat 3170 attcagcgca cgcagagaaaattaattata tttctacaga gaaaatgaat ttgggatact 3230 aaagtagttt aagtctcctttactgaatgt aaggggggga tcgaaaagaa ggtatttttc 3290 caatcacagt gttatgtagtattgttctat ttttgtttac aaacatggaa aacagagtat 3350 ttctggcagc tctcgtacaaatgtgataat atattgctaa aatattttag atgttattat 3410 gctaatatag taggggttgaagaaaacaaa atagcttatt atagaattgc acatagttct 3470 gcccaaatta tgtgaaatgcttatgcttgt gtatatgtat aaattaatac acactacgtt 3530 aaaagcaaaa agatgtatatttgcatattt ttctaaagaa atatattatt catctttt 3588 12 490 PRT Homo sapiens12 Met Arg Phe Thr Phe Thr Ser Arg Cys Leu Ala Leu Phe Leu Leu Leu 1 510 15 Asn His Pro Thr Pro Ile Leu Pro Ala Phe Ser Asn Gln Thr Tyr Pro 2025 30 Thr Ile Glu Pro Lys Pro Phe Leu Tyr Val Val Gly Arg Lys Lys Met 3540 45 Met Asp Ala Gln Tyr Lys Cys Tyr Asp Arg Met Gln Gln Leu Pro Ala 5055 60 Tyr Gln Gly Glu Gly Pro Tyr Cys Asn Arg Thr Trp Asp Gly Trp Leu 6570 75 80 Cys Trp Asp Asp Thr Pro Ala Gly Val Leu Ser Tyr Gln Phe Cys Pro85 90 95 Asp Tyr Phe Pro Asp Phe Asp Pro Ser Glu Lys Val Thr Lys Tyr Cys100 105 110 Asp Glu Lys Gly Val Trp Phe Lys His Pro Glu Asn Asn Arg ThrTrp 115 120 125 Ser Asn Tyr Thr Met Cys Asn Ala Phe Thr Pro Glu Lys LeuLys Asn 130 135 140 Ala Tyr Val Leu Tyr Tyr Leu Ala Ile Val Gly His SerLeu Ser Ile 145 150 155 160 Phe Thr Leu Val Ile Phe Leu Gly Ile Phe ValPhe Phe Arg Lys Leu 165 170 175 Thr Thr Ile Phe Pro Leu Asn Trp Lys TyrArg Lys Ala Leu Ser Leu 180 185 190 Gly Cys Gln Arg Val Thr Leu His LysAsn Met Phe Leu Thr Tyr Ile 195 200 205 Leu Asn Ser Met Ile Ile Ile IleHis Leu Val Glu Val Val Pro Asn 210 215 220 Gly Glu Leu Val Arg Arg AspPro Val Ser Cys Lys Ile Leu His Phe 225 230 235 240 Phe His Gln Tyr MetMet Ala Cys Asn Tyr Phe Trp Met Leu Cys Glu 245 250 255 Gly Ile Tyr LeuHis Thr Leu Ile Val Val Ala Val Phe Thr Glu Lys 260 265 270 Gln Arg LeuArg Trp Tyr Tyr Leu Leu Gly Trp Gly Phe Pro Leu Val 275 280 285 Pro ThrThr Ile His Ala Ile Thr Arg Ala Val Tyr Phe Asn Asp Asn 290 295 300 CysTrp Leu Ser Val Glu Thr His Leu Leu Tyr Ile Ile His Gly Pro 305 310 315320 Val Met Ala Ala Leu Val Val Asn Phe Phe Phe Leu Leu Asn Ile Val 325330 335 Arg Val Leu Val Thr Lys Met Arg Glu Thr His Glu Ala Glu Ser His340 345 350 Met Tyr Leu Lys Ala Val Lys Ala Thr Met Ile Leu Val Pro LeuLeu 355 360 365 Gly Ile Gln Phe Val Val Phe Pro Trp Arg Pro Ser Asn LysMet Leu 370 375 380 Gly Lys Ile Tyr Asp Tyr Val Met His Ser Leu Ile HisPhe Gln Gly 385 390 395 400 Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys AsnAsn Glu Val Gln Thr 405 410 415 Thr Val Lys Arg Gln Trp Ala Gln Phe LysIle Gln Trp Asn Gln Arg 420 425 430 Trp Gly Arg Arg Pro Ser Asn Arg SerAla Arg Ala Ala Ala Ala Ala 435 440 445 Ala Glu Ala Gly Asp Ile Pro IleTyr Ile Cys His Gln Glu Pro Arg 450 455 460 Asn Glu Pro Ala Asn Asn GlnGly Glu Glu Ser Ala Glu Ile Ile Pro 465 470 475 480 Leu Asn Ile Ile GluGln Glu Ser Ser Ala 485 490 13 3416 DNA Homo sapiens CDS (52)..(594) 13gaattcgcgg ccgccagaat tccaggacaa agagatcttc aaaaatcaaa a atg agg 57 MetArg 1 ttc aca ttt aca agc cgg tgc ttg gca ctg ttt ctt ctt cta aat cac105 Phe Thr Phe Thr Ser Arg Cys Leu Ala Leu Phe Leu Leu Leu Asn His 5 1015 cca acc cca att ctt cct gcc ttt tca aat caa acc tat cca aca ata 153Pro Thr Pro Ile Leu Pro Ala Phe Ser Asn Gln Thr Tyr Pro Thr Ile 20 25 30gag ccc aag cca ttt ctt tac gtc gta gga cga aag aag atg atg gat 201 GluPro Lys Pro Phe Leu Tyr Val Val Gly Arg Lys Lys Met Met Asp 35 40 45 50gca cag tac aaa tgc tat gac cga atg cag cag tta ccc gca tac caa 249 AlaGln Tyr Lys Cys Tyr Asp Arg Met Gln Gln Leu Pro Ala Tyr Gln 55 60 65 ggagaa ggt cca tat tgc aat cgc acc tgg gat gga tgg ctg tgc tgg 297 Gly GluGly Pro Tyr Cys Asn Arg Thr Trp Asp Gly Trp Leu Cys Trp 70 75 80 gat gacaca ccg gct gga gta ttg tcc tat cag ttc tgc cca gat tat 345 Asp Asp ThrPro Ala Gly Val Leu Ser Tyr Gln Phe Cys Pro Asp Tyr 85 90 95 ttt ccg gatttt gat cca tca gaa aag gtt aca aaa tac tgt gat gaa 393 Phe Pro Asp PheAsp Pro Ser Glu Lys Val Thr Lys Tyr Cys Asp Glu 100 105 110 aaa ggt gtttgg ttt aaa cat cct gaa aac aat cga acc tgg tcc aac 441 Lys Gly Val TrpPhe Lys His Pro Glu Asn Asn Arg Thr Trp Ser Asn 115 120 125 130 tat actatg tgc aat gct ttc act cct gag aaa ctg aag aat gca tat 489 Tyr Thr MetCys Asn Ala Phe Thr Pro Glu Lys Leu Lys Asn Ala Tyr 135 140 145 gtt ctgtac tat ttg gct att gtg ggt cat tct ttg tca att ttc acc 537 Val Leu TyrTyr Leu Ala Ile Val Gly His Ser Leu Ser Ile Phe Thr 150 155 160 cta gtgatt tcc ctg ggg att ttc gtg ttt ttc agt tct cat gtt tat 585 Leu Val IleSer Leu Gly Ile Phe Val Phe Phe Ser Ser His Val Tyr 165 170 175 cat gaataa cacgtgatcc taggagcctt ggctgccaaa gggtaaccct 634 His Glu 180gcacaagaac atgtttctta cttacattct gaattctatg attatcatca tccacctggt 694tgaagtagta cccaatggag agctcgtgcg aagggacccg gtgagctgca agattttgca 754ttttttccac cagtacatga tggcctgcaa ctatttctgg atgctctgtg aagggatcta 814tcttcataca ctcattgtcg tggctgtgtt tactgagaag caacgcttgc ggtggtatta 874tctcttgggc tgggggttcc cgctggtgcc aaccactatc catgctatta ccagggccgt 934gtacttcaat gacaactgct ggctgagtgt ggaaacccat ttgctttaca taatccatgg 994acctgtcatg gcggcacttg tggtcaattt cttctttttg ctcaacattg tccgggtgct 1054tgtgaccaaa atgagggaaa cccatgaggc ggaatcccac atgtacctga aggctgtgaa 1114ggccaccatg atccttgtgc ccctgctggg aatccagttt gtcgtctttc cctggagacc 1174ttccaacaag atgcttggga agatatatga ttacgtgatg cactctctga ttcatttcca 1234gggcttcttt gttgcgacca tctactgctt ctgcaacaat gaggtccaaa ccaccgtgaa 1294gcgccaatgg gcccaattca aaattcagtg gaaccagcgt tgggggaggc gcccctccaa 1354ccgctctgct cgcgctgcag ccgctgctgc ggaggctggc gacatcccaa tttacatctg 1414ccatcaggag ctgaggaatg aaccagccaa caaccaaggc gaggagagtg ctgagatcat 1474ccctttgaat atcatagagc aagagtcatc tgcttgaatg tgaaggcaaa cacagcatcg 1534tgatcactga gccatcattt cctgggagaa agaccatgca tttaaagtat tctccatcct 1594cccaggaacc gaacatatca tttgtgaaga attattcagt gaatttgtcc attgtaaatc 1654tgaagaaagt tattcttggt actgttgctt tgggagacag tctaggaatg gagtctccca 1714ctgcaacttg tgaactccat cattcatcca ggactgagat gcaaatgtca cagtaatgca 1774agcaaagtat caaagaaaaa caatgaaatt gacctagttc agatacaggg tgctccttgt 1834caatactgag ccatttatac ctttgaaata ttaaaatcac tgtcaatatt tttattttta 1894actctggatt ttgaattaga ttatttctgt atttggctat ggatctgatt tttaattttt 1954ttaaatttca gtcaattctg atgttactga gatgttttac catccttaca atgtaaacca 2014catgaactac gtgacctctg caagacaaag cggctttcta atagagagat tagtaaatat 2074gtgaagaaaa agacctgcat ttggcaggaa gatgtatgct ttgaatgcaa aagaaattta 2134gagtcaattt gctgaaaaca ttacatgctc agcttggttt tggacaagcc tgtccattgg 2194gcaggaccta gctgttgtaa agaattggtc ttaatgttga atgtattttg gttgctgatg 2254tttataaact gagaggtcac aaagaatcta tcactaaaaa tttttacaaa actgccaaaa 2314atataattct tagtggaaga caatactccc tttaaagaga gtttgccact cccctaaact 2374ccaggattta taaagcaaat tactccaagg tttataaagc agattacctc ttgcccttgg 2434gtgctatcta gcagtaaaag ataaatttgt tgaatattgg taattaaaag actccacata 2494agtccattaa ctgctttcca cccagcttca aagcttaaaa agagctcagg cttttccagg 2554aagatccagg agggctaatt agaaatcaac ttgtggttga ccgcttgttt cttgttatta 2614ccaaacagga ggggaaaaaa ttaactgctc caaatttaac cataaatcaa ttcatgttta 2674acgtttctca ttaaaatcca gtattatatt atcatatctc tctttacttc ccagtataag 2734atttttgaaa atcctgaata aaccagtatc gttactggca cctgaaatta atttgtgaat 2794ttgcaacagt aatcagagtt accattattt aatttgtatg ctaaatgagg aggtacattg 2854aaaccctcca aatctccagt ctcatctatg tcatattttg ccactgcctt tcagaagtga 2914tttagttgtg gaaagataat aaattgattt gttatggtta catatttagc gcacccagag 2974aaaattaatt atatttctac agagaaaatg aatttgggat actaaagtag tttaagtctc 3034ctttactgaa tgtaaggggg ggatcgaaaa gaaggtattt ttccaatcac agtgttatgt 3094agtattgttc tatttttgtt tacaaacatg gaaaacagag tatttctggc agctgtggta 3154caaatgtgat aatatattgc taaaatattt tagatgttat tatgctaata tagtaggggt 3214tgaagaaaac aaaatagctt attatagaat tgcacatagt tctgcccaaa ttatgtgaaa 3274tgcttatgct tgtgtatatg tataaattaa tacagagtac gttaaaagca aaaagatgta 3334tatttgcata tttttctaaa gaaatatatt attcatcttt tcattcaaaa aaaaaaaaaa 3394agagctcaat tcccggggat cc 3416 14 180 PRT Homo sapiens 14 Met Arg Phe ThrPhe Thr Ser Arg Cys Leu Ala Leu Phe Leu Leu Leu 1 5 10 15 Asn His ProThr Pro Ile Leu Pro Ala Phe Ser Asn Gln Thr Tyr Pro 20 25 30 Thr Ile GluPro Lys Pro Phe Leu Tyr Val Val Gly Arg Lys Lys Met 35 40 45 Met Asp AlaGln Tyr Lys Cys Tyr Asp Arg Met Gln Gln Leu Pro Ala 50 55 60 Tyr Gln GlyGlu Gly Pro Tyr Cys Asn Arg Thr Trp Asp Gly Trp Leu 65 70 75 80 Cys TrpAsp Asp Thr Pro Ala Gly Val Leu Ser Tyr Gln Phe Cys Pro 85 90 95 Asp TyrPhe Pro Asp Phe Asp Pro Ser Glu Lys Val Thr Lys Tyr Cys 100 105 110 AspGlu Lys Gly Val Trp Phe Lys His Pro Glu Asn Asn Arg Thr Trp 115 120 125Ser Asn Tyr Thr Met Cys Asn Ala Phe Thr Pro Glu Lys Leu Lys Asn 130 135140 Ala Tyr Val Leu Tyr Tyr Leu Ala Ile Val Gly His Ser Leu Ser Ile 145150 155 160 Phe Thr Leu Val Ile Ser Leu Gly Ile Phe Val Phe Phe Ser SerHis 165 170 175 Val Tyr His Glu 180 15 1493 DNA Homo sapiens CDS(11)..(1483) 15 gaattccacc atg agg ttc aca ttt acc tcg agg tgc tta gcgctg ttt 49 Met Arg Phe Thr Phe Thr Ser Arg Cys Leu Ala Leu Phe 1 5 10ctt ctt cta aat cac cca acc cca att cta cct gcc ttt tcg aat caa 97 LeuLeu Leu Asn His Pro Thr Pro Ile Leu Pro Ala Phe Ser Asn Gln 15 20 25 acctat cca acg atc gag ccc aag cca ttt ctt tac gtc gtc ggc cga 145 Thr TyrPro Thr Ile Glu Pro Lys Pro Phe Leu Tyr Val Val Gly Arg 30 35 40 45 aagaag atg atg gat gcg cag tac aaa tgc tat gac cga atg cag caa 193 Lys LysMet Met Asp Ala Gln Tyr Lys Cys Tyr Asp Arg Met Gln Gln 50 55 60 ttg cccgca tac caa gga gaa ggt cca tat tgc aat cgt acg tgg gat 241 Leu Pro AlaTyr Gln Gly Glu Gly Pro Tyr Cys Asn Arg Thr Trp Asp 65 70 75 gga tgg ctgtgc tgg gat gac acg ccg gct gga gtc tta agc tat cag 289 Gly Trp Leu CysTrp Asp Asp Thr Pro Ala Gly Val Leu Ser Tyr Gln 80 85 90 ttc tgc cca gattat ttt ccg gat ttt gat cca tca gaa aag gtt aca 337 Phe Cys Pro Asp TyrPhe Pro Asp Phe Asp Pro Ser Glu Lys Val Thr 95 100 105 aag tac tgt gatgaa aaa ggt gtt tgg ttt aaa cat cct gaa aac aat 385 Lys Tyr Cys Asp GluLys Gly Val Trp Phe Lys His Pro Glu Asn Asn 110 115 120 125 cgc acg tggtcc aac tat act atg tgc aat gct ttc act cct gag aaa 433 Arg Thr Trp SerAsn Tyr Thr Met Cys Asn Ala Phe Thr Pro Glu Lys 130 135 140 ctg aaa aatgca tac gtt ctg tac tat ttg gct att gtg ggt cat tct 481 Leu Lys Asn AlaTyr Val Leu Tyr Tyr Leu Ala Ile Val Gly His Ser 145 150 155 tta tcg attttc acc cta gtg ata tcc ctc ggg att ttc gtg ttt ttc 529 Leu Ser Ile PheThr Leu Val Ile Ser Leu Gly Ile Phe Val Phe Phe 160 165 170 aga aag cttaca act att ttt cca ttg aat tgg aaa tat agg aag gcc 577 Arg Lys Leu ThrThr Ile Phe Pro Leu Asn Trp Lys Tyr Arg Lys Ala 175 180 185 ttg tcc ttaggc tgc caa agg gta acc ctg cac aag aac atg ttt ctt 625 Leu Ser Leu GlyCys Gln Arg Val Thr Leu His Lys Asn Met Phe Leu 190 195 200 205 acg tacatt cta aat tct atg atc atc atc atc cac ctg gtg gag gta 673 Thr Tyr IleLeu Asn Ser Met Ile Ile Ile Ile His Leu Val Glu Val 210 215 220 gta cccaat gga gag ctc gtg cga agg gac ccg gtc agc tgc aag att 721 Val Pro AsnGly Glu Leu Val Arg Arg Asp Pro Val Ser Cys Lys Ile 225 230 235 ttg catttt ttc cac cag tac atg atg gca tgc aac tat ttc tgg atg 769 Leu His PhePhe His Gln Tyr Met Met Ala Cys Asn Tyr Phe Trp Met 240 245 250 ctc tgtgaa ggg atc tat ctt cat aca ctc att gtc gtg gct gtg ttt 817 Leu Cys GluGly Ile Tyr Leu His Thr Leu Ile Val Val Ala Val Phe 255 260 265 act gagaag caa cgt cta cgg tgg tat tat ctc ttg ggc tgg ggg ttc 865 Thr Glu LysGln Arg Leu Arg Trp Tyr Tyr Leu Leu Gly Trp Gly Phe 270 275 280 285 ccgctg gta cca acc act atc cat gct att acg cgc gcc gtg tac ttc 913 Pro LeuVal Pro Thr Thr Ile His Ala Ile Thr Arg Ala Val Tyr Phe 290 295 300 aatgac aac tgc tgg ctg agt gtg gaa acc cat ttg ctt tac ata atc 961 Asn AspAsn Cys Trp Leu Ser Val Glu Thr His Leu Leu Tyr Ile Ile 305 310 315 catgga ccg gtc atg gcg gca cta gtg gtg aat ttc ttc ttt ttg ctc 1009 His GlyPro Val Met Ala Ala Leu Val Val Asn Phe Phe Phe Leu Leu 320 325 330 aacatt gta cgc gtg ctt gtg acc aaa atg agg gaa act cat gag gcg 1057 Asn IleVal Arg Val Leu Val Thr Lys Met Arg Glu Thr His Glu Ala 335 340 345 gaatcc cac atg tac ctg aag gcc gtg aag gcc acc atg atc ctt gtg 1105 Glu SerHis Met Tyr Leu Lys Ala Val Lys Ala Thr Met Ile Leu Val 350 355 360 365ccc ctg ctg ggg atc cag ttt gtc gtc ttt ccc tgg cgc cct tcc aac 1153 ProLeu Leu Gly Ile Gln Phe Val Val Phe Pro Trp Arg Pro Ser Asn 370 375 380aag atg ctt ggg aag atc tat gat tac gtg atg cac tca tta att cat 1201 LysMet Leu Gly Lys Ile Tyr Asp Tyr Val Met His Ser Leu Ile His 385 390 395ttc cag ggc ttc ttt gtg gcc acc atc tac tgc ttc tgc aac aat gag 1249 PheGln Gly Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn Asn Glu 400 405 410gtc caa acc acc gtg aag cgc caa tgg gcc caa ttc aaa att cag tgg 1297 ValGln Thr Thr Val Lys Arg Gln Trp Ala Gln Phe Lys Ile Gln Trp 415 420 425aac cag cgt tgg gga aga cgc ccc tcc aac cgc agt gca cgc gct gca 1345 AsnGln Arg Trp Gly Arg Arg Pro Ser Asn Arg Ser Ala Arg Ala Ala 430 435 440445 gcc gct gct gcg gag gct ggc gac atc cca att tac ata tgc cat cag 1393Ala Ala Ala Ala Glu Ala Gly Asp Ile Pro Ile Tyr Ile Cys His Gln 450 455460 gag cct agg aat gaa cca gcc aac aac caa ggc gag gag tcc gcg gag 1441Glu Pro Arg Asn Glu Pro Ala Asn Asn Gln Gly Glu Glu Ser Ala Glu 465 470475 atc atc cct ttg aat att ata gag caa gag tca tct gct tga 1483 Ile IlePro Leu Asn Ile Ile Glu Gln Glu Ser Ser Ala 480 485 490 tagcggccgc 149316 490 PRT Homo sapiens 16 Met Arg Phe Thr Phe Thr Ser Arg Cys Leu AlaLeu Phe Leu Leu Leu 1 5 10 15 Asn His Pro Thr Pro Ile Leu Pro Ala PheSer Asn Gln Thr Tyr Pro 20 25 30 Thr Ile Glu Pro Lys Pro Phe Leu Tyr ValVal Gly Arg Lys Lys Met 35 40 45 Met Asp Ala Gln Tyr Lys Cys Tyr Asp ArgMet Gln Gln Leu Pro Ala 50 55 60 Tyr Gln Gly Glu Gly Pro Tyr Cys Asn ArgThr Trp Asp Gly Trp Leu 65 70 75 80 Cys Trp Asp Asp Thr Pro Ala Gly ValLeu Ser Tyr Gln Phe Cys Pro 85 90 95 Asp Tyr Phe Pro Asp Phe Asp Pro SerGlu Lys Val Thr Lys Tyr Cys 100 105 110 Asp Glu Lys Gly Val Trp Phe LysHis Pro Glu Asn Asn Arg Thr Trp 115 120 125 Ser Asn Tyr Thr Met Cys AsnAla Phe Thr Pro Glu Lys Leu Lys Asn 130 135 140 Ala Tyr Val Leu Tyr TyrLeu Ala Ile Val Gly His Ser Leu Ser Ile 145 150 155 160 Phe Thr Leu ValIle Ser Leu Gly Ile Phe Val Phe Phe Arg Lys Leu 165 170 175 Thr Thr IlePhe Pro Leu Asn Trp Lys Tyr Arg Lys Ala Leu Ser Leu 180 185 190 Gly CysGln Arg Val Thr Leu His Lys Asn Met Phe Leu Thr Tyr Ile 195 200 205 LeuAsn Ser Met Ile Ile Ile Ile His Leu Val Glu Val Val Pro Asn 210 215 220Gly Glu Leu Val Arg Arg Asp Pro Val Ser Cys Lys Ile Leu His Phe 225 230235 240 Phe His Gln Tyr Met Met Ala Cys Asn Tyr Phe Trp Met Leu Cys Glu245 250 255 Gly Ile Tyr Leu His Thr Leu Ile Val Val Ala Val Phe Thr GluLys 260 265 270 Gln Arg Leu Arg Trp Tyr Tyr Leu Leu Gly Trp Gly Phe ProLeu Val 275 280 285 Pro Thr Thr Ile His Ala Ile Thr Arg Ala Val Tyr PheAsn Asp Asn 290 295 300 Cys Trp Leu Ser Val Glu Thr His Leu Leu Tyr IleIle His Gly Pro 305 310 315 320 Val Met Ala Ala Leu Val Val Asn Phe PhePhe Leu Leu Asn Ile Val 325 330 335 Arg Val Leu Val Thr Lys Met Arg GluThr His Glu Ala Glu Ser His 340 345 350 Met Tyr Leu Lys Ala Val Lys AlaThr Met Ile Leu Val Pro Leu Leu 355 360 365 Gly Ile Gln Phe Val Val PhePro Trp Arg Pro Ser Asn Lys Met Leu 370 375 380 Gly Lys Ile Tyr Asp TyrVal Met His Ser Leu Ile His Phe Gln Gly 385 390 395 400 Phe Phe Val AlaThr Ile Tyr Cys Phe Cys Asn Asn Glu Val Gln Thr 405 410 415 Thr Val LysArg Gln Trp Ala Gln Phe Lys Ile Gln Trp Asn Gln Arg 420 425 430 Trp GlyArg Arg Pro Ser Asn Arg Ser Ala Arg Ala Ala Ala Ala Ala 435 440 445 AlaGlu Ala Gly Asp Ile Pro Ile Tyr Ile Cys His Gln Glu Pro Arg 450 455 460Asn Glu Pro Ala Asn Asn Gln Gly Glu Glu Ser Ala Glu Ile Ile Pro 465 470475 480 Leu Asn Ile Ile Glu Gln Glu Ser Ser Ala 485 490 17 1472 DNACavia porcellus CDS (20)..(1456) 17 cgcccgggca ggtccgaaa atg agg ttc actttt aca cgc cag ttc ttg gca 52 Met Arg Phe Thr Phe Thr Arg Gln Phe LeuAla 1 5 10 ttc ttc atc ctc atc agt aac cca gct tca att ctt ccc agg tctgag 100 Phe Phe Ile Leu Ile Ser Asn Pro Ala Ser Ile Leu Pro Arg Ser Glu15 20 25 aat ctc acc ttt ccg aca ttt gag cct gag cca tat ctg tat tct gtc148 Asn Leu Thr Phe Pro Thr Phe Glu Pro Glu Pro Tyr Leu Tyr Ser Val 3035 40 gga cgc aag aag ttg gtg gac gct cag tac agg tgc tat gac cgt atg196 Gly Arg Lys Lys Leu Val Asp Ala Gln Tyr Arg Cys Tyr Asp Arg Met 4550 55 caa cag tta cct cct tat gaa gga gaa ggc ccc tac tgc aat cgg acg244 Gln Gln Leu Pro Pro Tyr Glu Gly Glu Gly Pro Tyr Cys Asn Arg Thr 6065 70 75 tgg gac ggg tgg atg tgc tgg gac gat act cca gcc gga gta ctc tcc292 Trp Asp Gly Trp Met Cys Trp Asp Asp Thr Pro Ala Gly Val Leu Ser 8085 90 gtt cag tta tgc ccg gat tac ttt cca gac ttt gat cca aca gaa aag340 Val Gln Leu Cys Pro Asp Tyr Phe Pro Asp Phe Asp Pro Thr Glu Lys 95100 105 gtt aca aag tac tgc gat gaa agt ggg gtt tgg ttt aag cat cct gag388 Val Thr Lys Tyr Cys Asp Glu Ser Gly Val Trp Phe Lys His Pro Glu 110115 120 aac aat cga acc tgg tcc aac tat acc ttg tgc aac gcc ttt act cct436 Asn Asn Arg Thr Trp Ser Asn Tyr Thr Leu Cys Asn Ala Phe Thr Pro 125130 135 gag aag ctg cag aat gct tat gtt ctg tac tat ctg gct atc gtg ggt484 Glu Lys Leu Gln Asn Ala Tyr Val Leu Tyr Tyr Leu Ala Ile Val Gly 140145 150 155 cac tct atg tcg att atc acc ttg gtg gtt tct ctg gga att tttgtg 532 His Ser Met Ser Ile Ile Thr Leu Val Val Ser Leu Gly Ile Phe Val160 165 170 tat ttc agg agt ctt ggc tgc cag cgg gtg acc ctg cac aag aacatg 580 Tyr Phe Arg Ser Leu Gly Cys Gln Arg Val Thr Leu His Lys Asn Met175 180 185 ttc ctg acg tac att ctg aac tcc atg atc atc atc atc cac ctggtt 628 Phe Leu Thr Tyr Ile Leu Asn Ser Met Ile Ile Ile Ile His Leu Val190 195 200 gag gtc gtg ccc aat gga gag ctg gtg cgc aag gac ccg gtg agctgc 676 Glu Val Val Pro Asn Gly Glu Leu Val Arg Lys Asp Pro Val Ser Cys205 210 215 aag att ttg cac ttc ttt cac cag tac atg atg gcc tgc aat tatttc 724 Lys Ile Leu His Phe Phe His Gln Tyr Met Met Ala Cys Asn Tyr Phe220 225 230 235 tgg atg ctc tgt gaa ggg atc tat ctt cat acg ctc att gtggtg tct 772 Trp Met Leu Cys Glu Gly Ile Tyr Leu His Thr Leu Ile Val ValSer 240 245 250 gtg ttt aac gag gca aag cat ctg cgc tgg tat tat ctc ctgggc tgg 820 Val Phe Asn Glu Ala Lys His Leu Arg Trp Tyr Tyr Leu Leu GlyTrp 255 260 265 ggg ttc cca ctg gtg cca acc act atc cat gct att act cgggca ctg 868 Gly Phe Pro Leu Val Pro Thr Thr Ile His Ala Ile Thr Arg AlaLeu 270 275 280 tac ttc aat gac aac tgc tgg ata agt gtg gat acc cac ttgctg tac 916 Tyr Phe Asn Asp Asn Cys Trp Ile Ser Val Asp Thr His Leu LeuTyr 285 290 295 atc atc cat ggc cct gtc atg gtg gcg ctg gtg gtc aat ttcttc ttt 964 Ile Ile His Gly Pro Val Met Val Ala Leu Val Val Asn Phe PhePhe 300 305 310 315 ttg ctc aac atc gtc cga gtg ctg gtg act aag atg agggaa acc cat 1012 Leu Leu Asn Ile Val Arg Val Leu Val Thr Lys Met Arg GluThr His 320 325 330 gag gcc gag tcc tac atg tac ctg aag gcc gtg aag gccacc atg atc 1060 Glu Ala Glu Ser Tyr Met Tyr Leu Lys Ala Val Lys Ala ThrMet Ile 335 340 345 ctg gtg ccc ctg ctg gga atc cag ttt gtc gtc ttt ccctgg agg cct 1108 Leu Val Pro Leu Leu Gly Ile Gln Phe Val Val Phe Pro TrpArg Pro 350 355 360 tcc aac aaa gtg ctt ggg aag atc tat gac tac ttc atgcac tct ctg 1156 Ser Asn Lys Val Leu Gly Lys Ile Tyr Asp Tyr Phe Met HisSer Leu 365 370 375 att cac ttc cag gga ttc ttc gtt gcg act atc tac tgcttc tgc aac 1204 Ile His Phe Gln Gly Phe Phe Val Ala Thr Ile Tyr Cys PheCys Asn 380 385 390 395 aac gag gtc caa act acc ctg aag cgc cag tgg gcccag ttc aag atc 1252 Asn Glu Val Gln Thr Thr Leu Lys Arg Gln Trp Ala GlnPhe Lys Ile 400 405 410 caa tgg aac cag cgc tgg gga acc cgc ccc tcc aaccgc tcg gct gct 1300 Gln Trp Asn Gln Arg Trp Gly Thr Arg Pro Ser Asn ArgSer Ala Ala 415 420 425 gct cga gct gca gct gct gct gct gag gct ggc ggtgac aat atc cca 1348 Ala Arg Ala Ala Ala Ala Ala Ala Glu Ala Gly Gly AspAsn Ile Pro 430 435 440 gtt tac atc tgc cac cag gag ccg agg aat gat ccaccc aac aac caa 1396 Val Tyr Ile Cys His Gln Glu Pro Arg Asn Asp Pro ProAsn Asn Gln 445 450 455 ggc gag gag ggt gct gag atg atc gtt ttg aac atcatc gag aaa gag 1444 Gly Glu Glu Gly Ala Glu Met Ile Val Leu Asn Ile IleGlu Lys Glu 460 465 470 475 tca tct gct tga agtgtaaata cacaca 1472 SerSer Ala 18 478 PRT Cavia porcellus 18 Met Arg Phe Thr Phe Thr Arg GlnPhe Leu Ala Phe Phe Ile Leu Ile 1 5 10 15 Ser Asn Pro Ala Ser Ile LeuPro Arg Ser Glu Asn Leu Thr Phe Pro 20 25 30 Thr Phe Glu Pro Glu Pro TyrLeu Tyr Ser Val Gly Arg Lys Lys Leu 35 40 45 Val Asp Ala Gln Tyr Arg CysTyr Asp Arg Met Gln Gln Leu Pro Pro 50 55 60 Tyr Glu Gly Glu Gly Pro TyrCys Asn Arg Thr Trp Asp Gly Trp Met 65 70 75 80 Cys Trp Asp Asp Thr ProAla Gly Val Leu Ser Val Gln Leu Cys Pro 85 90 95 Asp Tyr Phe Pro Asp PheAsp Pro Thr Glu Lys Val Thr Lys Tyr Cys 100 105 110 Asp Glu Ser Gly ValTrp Phe Lys His Pro Glu Asn Asn Arg Thr Trp 115 120 125 Ser Asn Tyr ThrLeu Cys Asn Ala Phe Thr Pro Glu Lys Leu Gln Asn 130 135 140 Ala Tyr ValLeu Tyr Tyr Leu Ala Ile Val Gly His Ser Met Ser Ile 145 150 155 160 IleThr Leu Val Val Ser Leu Gly Ile Phe Val Tyr Phe Arg Ser Leu 165 170 175Gly Cys Gln Arg Val Thr Leu His Lys Asn Met Phe Leu Thr Tyr Ile 180 185190 Leu Asn Ser Met Ile Ile Ile Ile His Leu Val Glu Val Val Pro Asn 195200 205 Gly Glu Leu Val Arg Lys Asp Pro Val Ser Cys Lys Ile Leu His Phe210 215 220 Phe His Gln Tyr Met Met Ala Cys Asn Tyr Phe Trp Met Leu CysGlu 225 230 235 240 Gly Ile Tyr Leu His Thr Leu Ile Val Val Ser Val PheAsn Glu Ala 245 250 255 Lys His Leu Arg Trp Tyr Tyr Leu Leu Gly Trp GlyPhe Pro Leu Val 260 265 270 Pro Thr Thr Ile His Ala Ile Thr Arg Ala LeuTyr Phe Asn Asp Asn 275 280 285 Cys Trp Ile Ser Val Asp Thr His Leu LeuTyr Ile Ile His Gly Pro 290 295 300 Val Met Val Ala Leu Val Val Asn PhePhe Phe Leu Leu Asn Ile Val 305 310 315 320 Arg Val Leu Val Thr Lys MetArg Glu Thr His Glu Ala Glu Ser Tyr 325 330 335 Met Tyr Leu Lys Ala ValLys Ala Thr Met Ile Leu Val Pro Leu Leu 340 345 350 Gly Ile Gln Phe ValVal Phe Pro Trp Arg Pro Ser Asn Lys Val Leu 355 360 365 Gly Lys Ile TyrAsp Tyr Phe Met His Ser Leu Ile His Phe Gln Gly 370 375 380 Phe Phe ValAla Thr Ile Tyr Cys Phe Cys Asn Asn Glu Val Gln Thr 385 390 395 400 ThrLeu Lys Arg Gln Trp Ala Gln Phe Lys Ile Gln Trp Asn Gln Arg 405 410 415Trp Gly Thr Arg Pro Ser Asn Arg Ser Ala Ala Ala Arg Ala Ala Ala 420 425430 Ala Ala Ala Glu Ala Gly Gly Asp Asn Ile Pro Val Tyr Ile Cys His 435440 445 Gln Glu Pro Arg Asn Asp Pro Pro Asn Asn Gln Gly Glu Glu Gly Ala450 455 460 Glu Met Ile Val Leu Asn Ile Ile Glu Lys Glu Ser Ser Ala 465470 475 19 3555 DNA Oryctolagus cuniculus CDS (276)..(1700) 19tcagcccctc gctcgctggc ttgcggacct ccgtggggag cagagaagcg cgcagagtgc 60ctcgcctcgc cctgggctgc cgccgcctgc ccaggagatg ggcgcccgtg cctgacttgc 120taccaccacc tgagaacgcc cttcgcgttc cctgggttgt gcccgccgcg actgagagaa 180ttcaggaacc caacactttg attaaggaga agactgaggc agagatggcg catctccctc 240ccagcaggat gaagagagat cttcagaaac caaaa atg aag ttc act ctt acg 293 MetLys Phe Thr Leu Thr 1 5 tgg cgg tgc ttt gcg ctg ttc ctc ctt cta cat caacca aca cca gtt 341 Trp Arg Cys Phe Ala Leu Phe Leu Leu Leu His Gln ProThr Pro Val 10 15 20 aac cct gcc tct tca aat gac acc cat cca aca gtt gaacct gag cca 389 Asn Pro Ala Ser Ser Asn Asp Thr His Pro Thr Val Glu ProGlu Pro 25 30 35 ttt ctg tac gtc ata gga cgc aag aag ctg atg gat gca cagtac aaa 437 Phe Leu Tyr Val Ile Gly Arg Lys Lys Leu Met Asp Ala Gln TyrLys 40 45 50 tgc tat gac cga atg gaa cag cta cct cca tac caa gga gaa ggtccc 485 Cys Tyr Asp Arg Met Glu Gln Leu Pro Pro Tyr Gln Gly Glu Gly Pro55 60 65 70 tac tgc aac cgg acc tgg gat gga tgg atg tgc tgg gac gac actcca 533 Tyr Cys Asn Arg Thr Trp Asp Gly Trp Met Cys Trp Asp Asp Thr Pro75 80 85 gct gga gtc ctg ggc ttc cag tac tgc cca gat tat ttt cca gac ttc581 Ala Gly Val Leu Gly Phe Gln Tyr Cys Pro Asp Tyr Phe Pro Asp Phe 9095 100 gat cca aca gaa aag gtt aca aaa tat tgt gat gaa aca gga gtt tgg629 Asp Pro Thr Glu Lys Val Thr Lys Tyr Cys Asp Glu Thr Gly Val Trp 105110 115 ttt aaa cac cct ggg aac aac caa acc tgg tcc aac tat act atg tgt677 Phe Lys His Pro Gly Asn Asn Gln Thr Trp Ser Asn Tyr Thr Met Cys 120125 130 aat gcg ttc act cct gag aaa cta cag aat gcg tac gtg cta tac tat725 Asn Ala Phe Thr Pro Glu Lys Leu Gln Asn Ala Tyr Val Leu Tyr Tyr 135140 145 150 ctg gct att gtg ggt cat tct ctg tcg att ttc acc ttg gtg atttcc 773 Leu Ala Ile Val Gly His Ser Leu Ser Ile Phe Thr Leu Val Ile Ser155 160 165 ttg ggg att ttt aag tgt ttc agg agt ctt ggt tgc cag cgg gtgacc 821 Leu Gly Ile Phe Lys Cys Phe Arg Ser Leu Gly Cys Gln Arg Val Thr170 175 180 ctg cat aag aac atg ttt ctg act tac att ctg aac tct atg attatc 869 Leu His Lys Asn Met Phe Leu Thr Tyr Ile Leu Asn Ser Met Ile Ile185 190 195 atc atc cac ctg gtt gaa gtt gtg ccc aac ggc gag ctg gtg agaagg 917 Ile Ile His Leu Val Glu Val Val Pro Asn Gly Glu Leu Val Arg Arg200 205 210 gat ccg gtg agc tgc aag gtt ctg cat ttt ttc cac cag tac atgatg 965 Asp Pro Val Ser Cys Lys Val Leu His Phe Phe His Gln Tyr Met Met215 220 225 230 tcc tgc aac tat ttc tgg atg ctc tgc gaa ggg atc tac ctgcac acg 1013 Ser Cys Asn Tyr Phe Trp Met Leu Cys Glu Gly Ile Tyr Leu HisThr 235 240 245 ctg atc gtg gtg gcc gtg ttt gcc aag cag cag cac ctg cgctgg tac 1061 Leu Ile Val Val Ala Val Phe Ala Lys Gln Gln His Leu Arg TrpTyr 250 255 260 tac ctc ctg ggc tgg ggg ttc cca ctg gtg cca acc act atccac gct 1109 Tyr Leu Leu Gly Trp Gly Phe Pro Leu Val Pro Thr Thr Ile HisAla 265 270 275 att act cga gca atc tac ttc aat gac aac tgc tgg atg agcgtg gag 1157 Ile Thr Arg Ala Ile Tyr Phe Asn Asp Asn Cys Trp Met Ser ValGlu 280 285 290 acc cat ctg ctt tac atc atc cat ggc cca gtg atg gca gctctg gtg 1205 Thr His Leu Leu Tyr Ile Ile His Gly Pro Val Met Ala Ala LeuVal 295 300 305 310 gtc aat ttc ttc ttt ttg ctc aac atc gtc cgg gtg ctagtg acc aag 1253 Val Asn Phe Phe Phe Leu Leu Asn Ile Val Arg Val Leu ValThr Lys 315 320 325 atg agg gaa acc ctc gaa gca gag tca cac atg tac ctgaag gct gtg 1301 Met Arg Glu Thr Leu Glu Ala Glu Ser His Met Tyr Leu LysAla Val 330 335 340 aag gcc acc atg atc ctg gtg ccc ctg ctg gga atc cagttt gtc gtc 1349 Lys Ala Thr Met Ile Leu Val Pro Leu Leu Gly Ile Gln PheVal Val 345 350 355 ttc ccc tgg agg ccc tcc aac aag att ctt ggg aag atctac gat tac 1397 Phe Pro Trp Arg Pro Ser Asn Lys Ile Leu Gly Lys Ile TyrAsp Tyr 360 365 370 ctc atg cac tcc ctg att cac ttc cag gga ttc ttt gtggcg act atc 1445 Leu Met His Ser Leu Ile His Phe Gln Gly Phe Phe Val AlaThr Ile 375 380 385 390 tac tgt ttc tgc aac aat gag gtc cag acc acc gtgaag cgc caa tgg 1493 Tyr Cys Phe Cys Asn Asn Glu Val Gln Thr Thr Val LysArg Gln Trp 395 400 405 gta cag ttt aaa atc caa tgg aac cag cgc tgg ggaaga cgc ccc gcc 1541 Val Gln Phe Lys Ile Gln Trp Asn Gln Arg Trp Gly ArgArg Pro Ala 410 415 420 cac cgt tcc gtt tcc cgc act gca gcc tcg gct gaggaa ggc ggc atc 1589 His Arg Ser Val Ser Arg Thr Ala Ala Ser Ala Glu GluGly Gly Ile 425 430 435 ccc gtt tat atc tac cac cag gag ccc agg aac gacccg gcc cac agc 1637 Pro Val Tyr Ile Tyr His Gln Glu Pro Arg Asn Asp ProAla His Ser 440 445 450 cta ggc gag gag ggt gcc gag atc atc ccc ttg aacatc atc gag caa 1685 Leu Gly Glu Glu Gly Ala Glu Ile Ile Pro Leu Asn IleIle Glu Gln 455 460 465 470 gag tca tct gct tga ctgtgaagcc aacacagcatcgtgctcact gagccttcat 1740 Glu Ser Ser Ala cacctggggg aaagatagaccatgcattta aagtgacccc cctcctccag gagctgagca 1800 tcatatttgt gaagaattagtaagtgaatt tgtcatagtg aatctggaga gagttatctt 1860 gtactattgc tctgggagacagtctaggaa tggagtctcc cactgcaact tgtgaactcc 1920 atcattcacc caagactgaaatgcagatga catagtacaa cgaaggtatc caagaaaaac 1980 acaaattgac ctagtgcagatacagggtgc tccttgttaa tcttgagcca tttatccttt 2040 gaaaaattaa aatcactgtcaatatttttt ctttttaact ctagattttg aatcagactt 2100 tctgtatttg gctatggatctgatttttaa tctttttatt tcgatcaatt ctgatgtatt 2160 gaaatgttct accatccatcgtgtaaaccg cacaaattac acgacctctg tggacacagt 2220 ggctttttaa catcaagatgactaagcacg ctggggaaga ggggaagaga cctgcatctg 2280 gcaggaagac ctaatctttgaaagacaaat ttagattcaa tttcgtggta atagtacgtg 2340 ttcagcttgg ctttggataagcctgtccat tgggcaggcc cagagtgctg taaggaattg 2400 gtctaatgtt ccgataatgcgtttgtttgc tgacattata aacggaggtc acaaagaatc 2460 catcacaaaa tttttcagaaaactgccaaa atcataattc ttcatggaac aaaatgctct 2520 taaaagagtt ttccactttcctaaactcca ggatttataa agcaaatcac tccaaggttt 2580 ataaagcaga ttacctcttgcccttgggtg ctatctagca gtaaaagaca aatttgttta 2640 agactggtaa ttacaagactccatataagt ccattaactg ccttccaccc tgcttcaaag 2700 cttaacaaga tctggcgttcccaggaagat tcagtagtgc taattggaaa tcagttgtgg 2760 ttgacctctt gtttgctgctattagcaaaa caggagggcc aaaatgtaac tcctacaagt 2820 ttaaccatat taattcatgttcaaagtaaa atttctcata aaaacccagt agtttatttc 2880 catcatctct ttagttctcgagcataagat cctttgaaaa tccctggata acctggaatt 2940 atcactggca tctgaatttaatttgtgaat ttgcaacagt aatagttctc atttaatttg 3000 gatgctaaat aagttgaaactttccaaatc tccagtctca tctatatcat ttatgccact 3060 gcctttcaga agcaattaagttgtggaaaa acaagcaatt gatttgctct ggttacacat 3120 ttagtgcact cagagaaacattctgtttct ccagtgaaaa tgtattttgg atactaaagt 3180 agtttaagtc tcctttactgcacgtaaggg aggaattgaa aagaaggtat tttttcaatc 3240 acagtgttat gtattaacattcctattttt gtttacagac atgaaaaaca gtatttcagg 3300 cagctctagt acaaatgtgataatatattg ctaaaatatt ttaggtgtta ttgtgctaat 3360 atagtagggg ctgaagaacacaaaatagct taaaatagaa ttcgacatag tgccaaaatg 3420 atgtgaaatg cttatgttatatatatatgt gtatgtgtgt ataaattaat agagtatgtg 3480 aaaagcaaaa agatgtatatttgcattatt tttctacaga aatatattgt tcatctcttc 3540 attcattaaa aaaaa 355520 474 PRT Oryctolagus cuniculus 20 Met Lys Phe Thr Leu Thr Trp Arg CysPhe Ala Leu Phe Leu Leu Leu 1 5 10 15 His Gln Pro Thr Pro Val Asn ProAla Ser Ser Asn Asp Thr His Pro 20 25 30 Thr Val Glu Pro Glu Pro Phe LeuTyr Val Ile Gly Arg Lys Lys Leu 35 40 45 Met Asp Ala Gln Tyr Lys Cys TyrAsp Arg Met Glu Gln Leu Pro Pro 50 55 60 Tyr Gln Gly Glu Gly Pro Tyr CysAsn Arg Thr Trp Asp Gly Trp Met 65 70 75 80 Cys Trp Asp Asp Thr Pro AlaGly Val Leu Gly Phe Gln Tyr Cys Pro 85 90 95 Asp Tyr Phe Pro Asp Phe AspPro Thr Glu Lys Val Thr Lys Tyr Cys 100 105 110 Asp Glu Thr Gly Val TrpPhe Lys His Pro Gly Asn Asn Gln Thr Trp 115 120 125 Ser Asn Tyr Thr MetCys Asn Ala Phe Thr Pro Glu Lys Leu Gln Asn 130 135 140 Ala Tyr Val LeuTyr Tyr Leu Ala Ile Val Gly His Ser Leu Ser Ile 145 150 155 160 Phe ThrLeu Val Ile Ser Leu Gly Ile Phe Lys Cys Phe Arg Ser Leu 165 170 175 GlyCys Gln Arg Val Thr Leu His Lys Asn Met Phe Leu Thr Tyr Ile 180 185 190Leu Asn Ser Met Ile Ile Ile Ile His Leu Val Glu Val Val Pro Asn 195 200205 Gly Glu Leu Val Arg Arg Asp Pro Val Ser Cys Lys Val Leu His Phe 210215 220 Phe His Gln Tyr Met Met Ser Cys Asn Tyr Phe Trp Met Leu Cys Glu225 230 235 240 Gly Ile Tyr Leu His Thr Leu Ile Val Val Ala Val Phe AlaLys Gln 245 250 255 Gln His Leu Arg Trp Tyr Tyr Leu Leu Gly Trp Gly PhePro Leu Val 260 265 270 Pro Thr Thr Ile His Ala Ile Thr Arg Ala Ile TyrPhe Asn Asp Asn 275 280 285 Cys Trp Met Ser Val Glu Thr His Leu Leu TyrIle Ile His Gly Pro 290 295 300 Val Met Ala Ala Leu Val Val Asn Phe PhePhe Leu Leu Asn Ile Val 305 310 315 320 Arg Val Leu Val Thr Lys Met ArgGlu Thr Leu Glu Ala Glu Ser His 325 330 335 Met Tyr Leu Lys Ala Val LysAla Thr Met Ile Leu Val Pro Leu Leu 340 345 350 Gly Ile Gln Phe Val ValPhe Pro Trp Arg Pro Ser Asn Lys Ile Leu 355 360 365 Gly Lys Ile Tyr AspTyr Leu Met His Ser Leu Ile His Phe Gln Gly 370 375 380 Phe Phe Val AlaThr Ile Tyr Cys Phe Cys Asn Asn Glu Val Gln Thr 385 390 395 400 Thr ValLys Arg Gln Trp Val Gln Phe Lys Ile Gln Trp Asn Gln Arg 405 410 415 TrpGly Arg Arg Pro Ala His Arg Ser Val Ser Arg Thr Ala Ala Ser 420 425 430Ala Glu Glu Gly Gly Ile Pro Val Tyr Ile Tyr His Gln Glu Pro Arg 435 440445 Asn Asp Pro Ala His Ser Leu Gly Glu Glu Gly Ala Glu Ile Ile Pro 450455 460 Leu Asn Ile Ile Glu Gln Glu Ser Ser Ala 465 470 21 3513 DNAOryctolagus cuniculus CDS (276)..(1658) 21 tcagcccctc gctcgctggcttgcggacct ccgtggggag cagagaagcg cgcagagtgc 60 ctcgcctcgc cctgggctgccgccgcctgc ccaggagatg ggcgcccgtg cctgacttgc 120 taccaccacc tgagaacgcccttcgcgttc cctgggttgt gcccgccgcg actgagagaa 180 ttcaggaacc caacactttgattaaggaga agactgaggc agagatggcg catctccctc 240 ccagcaggat gaagagagatcttcagaaac caaaa atg aag ttc act ctt acg 293 Met Lys Phe Thr Leu Thr 1 5tgg cgg tgc ttt gcg ctg ttc ctc ctt cta cat caa cca aca cca gtt 341 TrpArg Cys Phe Ala Leu Phe Leu Leu Leu His Gln Pro Thr Pro Val 10 15 20 aaccct gcc tct tca aat gac acc cat cca aca gtt gaa cct gag cca 389 Asn ProAla Ser Ser Asn Asp Thr His Pro Thr Val Glu Pro Glu Pro 25 30 35 ttt ctgtac gtc ata gga cgc aag aag ctg atg gat gca cag tac aaa 437 Phe Leu TyrVal Ile Gly Arg Lys Lys Leu Met Asp Ala Gln Tyr Lys 40 45 50 tgc tat gaccga atg gaa cag cta cct cca tac caa gga gaa ggt ccc 485 Cys Tyr Asp ArgMet Glu Gln Leu Pro Pro Tyr Gln Gly Glu Gly Pro 55 60 65 70 tac tgc aaccgg acc tgg gat gga tgg atg tgc tgg gac gac act cca 533 Tyr Cys Asn ArgThr Trp Asp Gly Trp Met Cys Trp Asp Asp Thr Pro 75 80 85 gct gga gtc ctgggc ttc cag tac tgc cca gat tat ttt cca gac ttc 581 Ala Gly Val Leu GlyPhe Gln Tyr Cys Pro Asp Tyr Phe Pro Asp Phe 90 95 100 gat cca aca gaaaag gtt aca aaa tat tgt gat gaa aca gga gtt tgg 629 Asp Pro Thr Glu LysVal Thr Lys Tyr Cys Asp Glu Thr Gly Val Trp 105 110 115 ttt aaa cac cctggg aac aac caa acc tgg tcc aac tat act atg tgt 677 Phe Lys His Pro GlyAsn Asn Gln Thr Trp Ser Asn Tyr Thr Met Cys 120 125 130 aat gcg ttc actcct gag aaa cta cag aat gcg tac gtg cta tac tat 725 Asn Ala Phe Thr ProGlu Lys Leu Gln Asn Ala Tyr Val Leu Tyr Tyr 135 140 145 150 ctg gct attgtg ggt cat tct ctg tcg att ttc acc ttg gtg att tcc 773 Leu Ala Ile ValGly His Ser Leu Ser Ile Phe Thr Leu Val Ile Ser 155 160 165 ttg ggg attttt aag tgt ttc agg agt ctt ggt tgc cag cgg gtg acc 821 Leu Gly Ile PheLys Cys Phe Arg Ser Leu Gly Cys Gln Arg Val Thr 170 175 180 ctg cat aagaac atg ttt ctg act tac att ctg aac tct atg att atc 869 Leu His Lys AsnMet Phe Leu Thr Tyr Ile Leu Asn Ser Met Ile Ile 185 190 195 atc atc cacctg gtt gaa gtt gtg ccc aac ggc gag ctg gtg aga agg 917 Ile Ile His LeuVal Glu Val Val Pro Asn Gly Glu Leu Val Arg Arg 200 205 210 gat ccg gtgagc tgc aag gtt ctg cat ttt ttc cac cag tac atg atg 965 Asp Pro Val SerCys Lys Val Leu His Phe Phe His Gln Tyr Met Met 215 220 225 230 tcc tgcaac tat ttc tgg atg ctc tgc gaa ggg atc tac ctg cac acg 1013 Ser Cys AsnTyr Phe Trp Met Leu Cys Glu Gly Ile Tyr Leu His Thr 235 240 245 ctg atcgtg gtg gcc gtg ttt gcc aag cag cag cac ctg cgc tgg tac 1061 Leu Ile ValVal Ala Val Phe Ala Lys Gln Gln His Leu Arg Trp Tyr 250 255 260 tac ctcctg ggc tgg ggg ttc cca ctg gtg cca acc act atc cac gct 1109 Tyr Leu LeuGly Trp Gly Phe Pro Leu Val Pro Thr Thr Ile His Ala 265 270 275 att actcga gca atc tac ttc aat gac aac tgc tgg atg agc gtg gag 1157 Ile Thr ArgAla Ile Tyr Phe Asn Asp Asn Cys Trp Met Ser Val Glu 280 285 290 acc catctg ctt tac atc atc cat ggc cca gtg atg gca gct ctg gtg 1205 Thr His LeuLeu Tyr Ile Ile His Gly Pro Val Met Ala Ala Leu Val 295 300 305 310 gtcaat ttc ttc ttt ttg ctc aac atc gtc cgg gtg cta gtg acc aag 1253 Val AsnPhe Phe Phe Leu Leu Asn Ile Val Arg Val Leu Val Thr Lys 315 320 325 atgagg gaa acc ctc gaa gca gag tca cac atg tac ctg aag gct gtg 1301 Met ArgGlu Thr Leu Glu Ala Glu Ser His Met Tyr Leu Lys Ala Val 330 335 340 aaggcc acc atg atc ctg gtg ccc ctg ctg gga atc cag ttt gtc gtc 1349 Lys AlaThr Met Ile Leu Val Pro Leu Leu Gly Ile Gln Phe Val Val 345 350 355 ttcccc tgg agg ccc tcc aac aag att ctt ggg aag atc tac gat tac 1397 Phe ProTrp Arg Pro Ser Asn Lys Ile Leu Gly Lys Ile Tyr Asp Tyr 360 365 370 ctcatg cac tcc ctg att cac ttc cag gtc cag acc acc gtg aag cgc 1445 Leu MetHis Ser Leu Ile His Phe Gln Val Gln Thr Thr Val Lys Arg 375 380 385 390caa tgg gta cag ttt aaa atc caa tgg aac cag cgc tgg gga aga cgc 1493 GlnTrp Val Gln Phe Lys Ile Gln Trp Asn Gln Arg Trp Gly Arg Arg 395 400 405ccc gcc cac cgt tcc gtt tcc cgc act gca gcc tcg gct gag gaa ggc 1541 ProAla His Arg Ser Val Ser Arg Thr Ala Ala Ser Ala Glu Glu Gly 410 415 420ggc atc ccc gtt tat atc tac cac cag gag ccc agg aac gac ccg gcc 1589 GlyIle Pro Val Tyr Ile Tyr His Gln Glu Pro Arg Asn Asp Pro Ala 425 430 435cac agc cta ggc gag gag ggt gcc gag atc atc ccc ttg aac atc atc 1637 HisSer Leu Gly Glu Glu Gly Ala Glu Ile Ile Pro Leu Asn Ile Ile 440 445 450gag caa gag tca tct gct tga ctgtgaagcc aacacagcat cgtgctcact 1688 GluGln Glu Ser Ser Ala 455 460 gagccttcat cacctggggg aaagatagac catgcatttaaagtgacccc cctcctccag 1748 gagctgagca tcatatttgt gaagaattag taagtgaatttgtcatagtg aatctggaga 1808 gagttatctt gtactattgc tctgggagac agtctaggaatggagtctcc cactgcaact 1868 tgtgaactcc atcattcacc caagactgaa atgcagatgacatagtacaa cgaaggtatc 1928 caagaaaaac acaaattgac ctagtgcaga tacagggtgctccttgttaa tcttgagcca 1988 tttatccttt gaaaaattaa aatcactgtc aatattttttctttttaact ctagattttg 2048 aatcagactt tctgtatttg gctatggatc tgatttttaatctttttatt tcgatcaatt 2108 ctgatgtatt gaaatgttct accatccatc gtgtaaaccgcacaaattac acgacctctg 2168 tggacacagt ggctttttaa catcaagatg actaagcacgctggggaaga ggggaagaga 2228 cctgcatctg gcaggaagac ctaatctttg aaagacaaatttagattcaa tttcgtggta 2288 atagtacgtg ttcagcttgg ctttggataa gcctgtccattgggcaggcc cagagtgctg 2348 taaggaattg gtctaatgtt ccgataatgc gtttgtttgctgacattata aacggaggtc 2408 acaaagaatc catcacaaaa tttttcagaa aactgccaaaatcataattc ttcatggaac 2468 aaaatgctct taaaagagtt ttccactttc ctaaactccaggatttataa agcaaatcac 2528 tccaaggttt ataaagcaga ttacctcttg cccttgggtgctatctagca gtaaaagaca 2588 aatttgttta agactggtaa ttacaagact ccatataagtccattaactg ccttccaccc 2648 tgcttcaaag cttaacaaga tctggcgttc ccaggaagattcagtagtgc taattggaaa 2708 tcagttgtgg ttgacctctt gtttgctgct attagcaaaacaggagggcc aaaatgtaac 2768 tcctacaagt ttaaccatat taattcatgt tcaaagtaaaatttctcata aaaacccagt 2828 agtttatttc catcatctct ttagttctcg agcataagatcctttgaaaa tccctggata 2888 acctggaatt atcactggca tctgaattta atttgtgaatttgcaacagt aatagttctc 2948 atttaatttg gatgctaaat aagttgaaac tttccaaatctccagtctca tctatatcat 3008 ttatgccact gcctttcaga agcaattaag ttgtggaaaaacaagcaatt gatttgctct 3068 ggttacacat ttagtgcact cagagaaaca ttctgtttctccagtgaaaa tgtattttgg 3128 atactaaagt agtttaagtc tcctttactg cacgtaagggaggaattgaa aagaaggtat 3188 tttttcaatc acagtgttat gtattaacat tcctatttttgtttacagac atgaaaaaca 3248 gtatttcagg cagctctagt acaaatgtga taatatattgctaaaatatt ttaggtgtta 3308 ttgtgctaat atagtagggg ctgaagaaca caaaatagcttaaaatagaa ttcgacatag 3368 tgccaaaatg atgtgaaatg cttatgttat atatatatgtgtatgtgtgt ataaattaat 3428 agagtatgtg aaaagcaaaa agatgtatat ttgcattatttttctacaga aatatattgt 3488 tcatctcttc attcattaaa aaaaa 3513 22 460 PRTOryctolagus cuniculus 22 Met Lys Phe Thr Leu Thr Trp Arg Cys Phe Ala LeuPhe Leu Leu Leu 1 5 10 15 His Gln Pro Thr Pro Val Asn Pro Ala Ser SerAsn Asp Thr His Pro 20 25 30 Thr Val Glu Pro Glu Pro Phe Leu Tyr Val IleGly Arg Lys Lys Leu 35 40 45 Met Asp Ala Gln Tyr Lys Cys Tyr Asp Arg MetGlu Gln Leu Pro Pro 50 55 60 Tyr Gln Gly Glu Gly Pro Tyr Cys Asn Arg ThrTrp Asp Gly Trp Met 65 70 75 80 Cys Trp Asp Asp Thr Pro Ala Gly Val LeuGly Phe Gln Tyr Cys Pro 85 90 95 Asp Tyr Phe Pro Asp Phe Asp Pro Thr GluLys Val Thr Lys Tyr Cys 100 105 110 Asp Glu Thr Gly Val Trp Phe Lys HisPro Gly Asn Asn Gln Thr Trp 115 120 125 Ser Asn Tyr Thr Met Cys Asn AlaPhe Thr Pro Glu Lys Leu Gln Asn 130 135 140 Ala Tyr Val Leu Tyr Tyr LeuAla Ile Val Gly His Ser Leu Ser Ile 145 150 155 160 Phe Thr Leu Val IleSer Leu Gly Ile Phe Lys Cys Phe Arg Ser Leu 165 170 175 Gly Cys Gln ArgVal Thr Leu His Lys Asn Met Phe Leu Thr Tyr Ile 180 185 190 Leu Asn SerMet Ile Ile Ile Ile His Leu Val Glu Val Val Pro Asn 195 200 205 Gly GluLeu Val Arg Arg Asp Pro Val Ser Cys Lys Val Leu His Phe 210 215 220 PheHis Gln Tyr Met Met Ser Cys Asn Tyr Phe Trp Met Leu Cys Glu 225 230 235240 Gly Ile Tyr Leu His Thr Leu Ile Val Val Ala Val Phe Ala Lys Gln 245250 255 Gln His Leu Arg Trp Tyr Tyr Leu Leu Gly Trp Gly Phe Pro Leu Val260 265 270 Pro Thr Thr Ile His Ala Ile Thr Arg Ala Ile Tyr Phe Asn AspAsn 275 280 285 Cys Trp Met Ser Val Glu Thr His Leu Leu Tyr Ile Ile HisGly Pro 290 295 300 Val Met Ala Ala Leu Val Val Asn Phe Phe Phe Leu LeuAsn Ile Val 305 310 315 320 Arg Val Leu Val Thr Lys Met Arg Glu Thr LeuGlu Ala Glu Ser His 325 330 335 Met Tyr Leu Lys Ala Val Lys Ala Thr MetIle Leu Val Pro Leu Leu 340 345 350 Gly Ile Gln Phe Val Val Phe Pro TrpArg Pro Ser Asn Lys Ile Leu 355 360 365 Gly Lys Ile Tyr Asp Tyr Leu MetHis Ser Leu Ile His Phe Gln Val 370 375 380 Gln Thr Thr Val Lys Arg GlnTrp Val Gln Phe Lys Ile Gln Trp Asn 385 390 395 400 Gln Arg Trp Gly ArgArg Pro Ala His Arg Ser Val Ser Arg Thr Ala 405 410 415 Ala Ser Ala GluGlu Gly Gly Ile Pro Val Tyr Ile Tyr His Gln Glu 420 425 430 Pro Arg AsnAsp Pro Ala His Ser Leu Gly Glu Glu Gly Ala Glu Ile 435 440 445 Ile ProLeu Asn Ile Ile Glu Gln Glu Ser Ser Ala 450 455 460 23 2144 DNA Susscrofa CDS (256)..(1704) 23 ggaaggacgg ccagcccccc agaccctggg agggctgcgccgcgcctttc tcggaccttc 60 ctgggctgga gaggtgcgcg ccgtccgcac ctcgcccaggggctggaatc tccaatccag 120 gagatgcgcg ctggagcctg agttcctgag tctctggagccaccacctgc gaatgacctt 180 cgcttccact gagctgtgcc cggcagccca gtgagactgctccaggactg acaagatcat 240 cttcaaaaat caaaa atg agg ttc aca ctt aca cgctgg tgc ttg acc ctc 291 Met Arg Phe Thr Leu Thr Arg Trp Cys Leu Thr Leu1 5 10 ttc atc ttt ctg aat cgg ccg tta cca gtt ctt cct gac agt gca gat339 Phe Ile Phe Leu Asn Arg Pro Leu Pro Val Leu Pro Asp Ser Ala Asp 1520 25 ggc gcc cac act cca aca ctt gag ccg gag cca ttt ctc tac att tta387 Gly Ala His Thr Pro Thr Leu Glu Pro Glu Pro Phe Leu Tyr Ile Leu 3035 40 ggg aaa cag cga atg tta gaa gca cag cac cga tgc tat gac cga atg435 Gly Lys Gln Arg Met Leu Glu Ala Gln His Arg Cys Tyr Asp Arg Met 4550 55 60 caa aag tta ccc cca tac caa gga gaa ggt ctg tac tgc aac cgt acc483 Gln Lys Leu Pro Pro Tyr Gln Gly Glu Gly Leu Tyr Cys Asn Arg Thr 6570 75 tgg gat gga tgg tcc tgc tgg gat gac aca ccg gct gga gtg ctc gcc531 Trp Asp Gly Trp Ser Cys Trp Asp Asp Thr Pro Ala Gly Val Leu Ala 8085 90 gag cag tac tgc cca gac tac ttt cct gac ttt gat gca gca gaa aaa579 Glu Gln Tyr Cys Pro Asp Tyr Phe Pro Asp Phe Asp Ala Ala Glu Lys 95100 105 gtt acc aag tac tgt ggt gaa gac ggg gat tgg tat cga cac cct gag627 Val Thr Lys Tyr Cys Gly Glu Asp Gly Asp Trp Tyr Arg His Pro Glu 110115 120 agc aac ata tcc tgg tcc aac tac act atg tgc aat gct ttc act cct675 Ser Asn Ile Ser Trp Ser Asn Tyr Thr Met Cys Asn Ala Phe Thr Pro 125130 135 140 gac aaa ctg cag aat gcg tac att ctg tac tac ttg gct att gtgggt 723 Asp Lys Leu Gln Asn Ala Tyr Ile Leu Tyr Tyr Leu Ala Ile Val Gly145 150 155 cat tct ttg tcg att ttg acc ttg ctg att tcc ctg ggg att ttcatg 771 His Ser Leu Ser Ile Leu Thr Leu Leu Ile Ser Leu Gly Ile Phe Met160 165 170 ttt ctc agg agc att agc tgc caa cgg gtg act ctg cac aag aacatg 819 Phe Leu Arg Ser Ile Ser Cys Gln Arg Val Thr Leu His Lys Asn Met175 180 185 ttt ctg act tac gtt ctg aat tct att atc atc atc gtc cac ctggtt 867 Phe Leu Thr Tyr Val Leu Asn Ser Ile Ile Ile Ile Val His Leu Val190 195 200 gtg atc gtg ccc aac gga gag ctg gtg aaa agg gat ccg ccg atctgc 915 Val Ile Val Pro Asn Gly Glu Leu Val Lys Arg Asp Pro Pro Ile Cys205 210 215 220 aag gtt ctg cac ttc ttc cac cag tac atg atg tca tgc aattat ttc 963 Lys Val Leu His Phe Phe His Gln Tyr Met Met Ser Cys Asn TyrPhe 225 230 235 tgg atg ctc tgc gag ggg gtc tat ctt cac act ctg atc gtggtg tcc 1011 Trp Met Leu Cys Glu Gly Val Tyr Leu His Thr Leu Ile Val ValSer 240 245 250 gtg ttc gct gag gga cag cgc ctg tgg tgg tat cat gtc ctgggc tgg 1059 Val Phe Ala Glu Gly Gln Arg Leu Trp Trp Tyr His Val Leu GlyTrp 255 260 265 ggg ttc ccg ctg att cca act act gct cat gcc att act agggca gtg 1107 Gly Phe Pro Leu Ile Pro Thr Thr Ala His Ala Ile Thr Arg AlaVal 270 275 280 ttg ttc aat gac aac tgc tgg ctg agt gtg gac acc aac ctgctt tac 1155 Leu Phe Asn Asp Asn Cys Trp Leu Ser Val Asp Thr Asn Leu LeuTyr 285 290 295 300 atc atc cac ggc cct gtc atg gca gca ctg gtg gtc aacttc ttc ttt 1203 Ile Ile His Gly Pro Val Met Ala Ala Leu Val Val Asn PhePhe Phe 305 310 315 ttg ctc aac atc ctc cgc gtg ctc gtg aag aaa ctg aaggaa agc cag 1251 Leu Leu Asn Ile Leu Arg Val Leu Val Lys Lys Leu Lys GluSer Gln 320 325 330 gag gcg gaa tcc cac atg tac ctg aag gca gtg cgg gccact ctg atc 1299 Glu Ala Glu Ser His Met Tyr Leu Lys Ala Val Arg Ala ThrLeu Ile 335 340 345 ttg gtg ccc ctg ctg ggc gtc cag ttt gtc gtc ctt ccctgg agg cct 1347 Leu Val Pro Leu Leu Gly Val Gln Phe Val Val Leu Pro TrpArg Pro 350 355 360 tcc acc cca ctg ctt ggg aag atc tac gac tac gtg gtgcac tct ctg 1395 Ser Thr Pro Leu Leu Gly Lys Ile Tyr Asp Tyr Val Val HisSer Leu 365 370 375 380 atc cac ttc cag gga ttc ttc gtt gcg att atc tactgc ttc tgc aac 1443 Ile His Phe Gln Gly Phe Phe Val Ala Ile Ile Tyr CysPhe Cys Asn 385 390 395 cac gag gtt cag gga gcc ctg aag cgc cag tgg aaccaa tac cag gcc 1491 His Glu Val Gln Gly Ala Leu Lys Arg Gln Trp Asn GlnTyr Gln Ala 400 405 410 cag cgc tgg gct ggc cgc cgc tcc acc cgg gcc gccaac gct gcg gcc 1539 Gln Arg Trp Ala Gly Arg Arg Ser Thr Arg Ala Ala AsnAla Ala Ala 415 420 425 gcc act gcc gct gcc gcc gcc gcc ctg gcc gag actgtg gag atc cct 1587 Ala Thr Ala Ala Ala Ala Ala Ala Leu Ala Glu Thr ValGlu Ile Pro 430 435 440 gtc tac atc tgc cac cag gag ccg agg gag gaa cccgcc ggc gaa gag 1635 Val Tyr Ile Cys His Gln Glu Pro Arg Glu Glu Pro AlaGly Glu Glu 445 450 455 460 ccg gtc gtg gag gtg gag ggt gtt gag gtc atcgcc atg gaa gtc ctc 1683 Pro Val Val Glu Val Glu Gly Val Glu Val Ile AlaMet Glu Val Leu 465 470 475 gag caa gag aca tct gcc tga acgtgacgcaaatacagcat cgtgatcact 1734 Glu Gln Glu Thr Ser Ala 480 gagtcctcacttcccgggag aaagaccaac cttgcatcca aaatgatttc catcctcccc 1794 gggggcaacatctcatttgt gagaattatt cagtgaattt ttccatcgtg aacctgaagt 1854 aagttttacttggtactctt gctacgggag acagtctcgg aatggagtct ccctctgcaa 1914 cccttgtgaactcctgtgaa ttccatcttt catccaggac tgagatacaa atgtcagagt 1974 aaagcaagcaaagatccaag taaaacgtaa ttcaagttga cctagttcag aagcagggtg 2034 ctccttgttaaccttgagcc atttatacct ttgaaaaatc aaaatcaccg tcagtatttt 2094 ttttttttctttttaactct aaactttgaa ttaggatatt tctatttggc 2144 24 482 PRT Sus scrofa24 Met Arg Phe Thr Leu Thr Arg Trp Cys Leu Thr Leu Phe Ile Phe Leu 1 510 15 Asn Arg Pro Leu Pro Val Leu Pro Asp Ser Ala Asp Gly Ala His Thr 2025 30 Pro Thr Leu Glu Pro Glu Pro Phe Leu Tyr Ile Leu Gly Lys Gln Arg 3540 45 Met Leu Glu Ala Gln His Arg Cys Tyr Asp Arg Met Gln Lys Leu Pro 5055 60 Pro Tyr Gln Gly Glu Gly Leu Tyr Cys Asn Arg Thr Trp Asp Gly Trp 6570 75 80 Ser Cys Trp Asp Asp Thr Pro Ala Gly Val Leu Ala Glu Gln Tyr Cys85 90 95 Pro Asp Tyr Phe Pro Asp Phe Asp Ala Ala Glu Lys Val Thr Lys Tyr100 105 110 Cys Gly Glu Asp Gly Asp Trp Tyr Arg His Pro Glu Ser Asn IleSer 115 120 125 Trp Ser Asn Tyr Thr Met Cys Asn Ala Phe Thr Pro Asp LysLeu Gln 130 135 140 Asn Ala Tyr Ile Leu Tyr Tyr Leu Ala Ile Val Gly HisSer Leu Ser 145 150 155 160 Ile Leu Thr Leu Leu Ile Ser Leu Gly Ile PheMet Phe Leu Arg Ser 165 170 175 Ile Ser Cys Gln Arg Val Thr Leu His LysAsn Met Phe Leu Thr Tyr 180 185 190 Val Leu Asn Ser Ile Ile Ile Ile ValHis Leu Val Val Ile Val Pro 195 200 205 Asn Gly Glu Leu Val Lys Arg AspPro Pro Ile Cys Lys Val Leu His 210 215 220 Phe Phe His Gln Tyr Met MetSer Cys Asn Tyr Phe Trp Met Leu Cys 225 230 235 240 Glu Gly Val Tyr LeuHis Thr Leu Ile Val Val Ser Val Phe Ala Glu 245 250 255 Gly Gln Arg LeuTrp Trp Tyr His Val Leu Gly Trp Gly Phe Pro Leu 260 265 270 Ile Pro ThrThr Ala His Ala Ile Thr Arg Ala Val Leu Phe Asn Asp 275 280 285 Asn CysTrp Leu Ser Val Asp Thr Asn Leu Leu Tyr Ile Ile His Gly 290 295 300 ProVal Met Ala Ala Leu Val Val Asn Phe Phe Phe Leu Leu Asn Ile 305 310 315320 Leu Arg Val Leu Val Lys Lys Leu Lys Glu Ser Gln Glu Ala Glu Ser 325330 335 His Met Tyr Leu Lys Ala Val Arg Ala Thr Leu Ile Leu Val Pro Leu340 345 350 Leu Gly Val Gln Phe Val Val Leu Pro Trp Arg Pro Ser Thr ProLeu 355 360 365 Leu Gly Lys Ile Tyr Asp Tyr Val Val His Ser Leu Ile HisPhe Gln 370 375 380 Gly Phe Phe Val Ala Ile Ile Tyr Cys Phe Cys Asn HisGlu Val Gln 385 390 395 400 Gly Ala Leu Lys Arg Gln Trp Asn Gln Tyr GlnAla Gln Arg Trp Ala 405 410 415 Gly Arg Arg Ser Thr Arg Ala Ala Asn AlaAla Ala Ala Thr Ala Ala 420 425 430 Ala Ala Ala Ala Leu Ala Glu Thr ValGlu Ile Pro Val Tyr Ile Cys 435 440 445 His Gln Glu Pro Arg Glu Glu ProAla Gly Glu Glu Pro Val Val Glu 450 455 460 Val Glu Gly Val Glu Val IleAla Met Glu Val Leu Glu Gln Glu Thr 465 470 475 480 Ser Ala 25 3410 DNARattus norvegicus CDS (297)..(1733) 25 ggcacgaggc agaggcaggc tctgcaaggagagccagtgg cccaagcccc tggacggact 60 gcagcttgca gacaactcct ggttggagaggtgcttctgc tcactctgag gttggcaccc 120 cctgcccagt gaagtctgag ttcctgagacatccagctag agaattcctg cgtccaccta 180 aggtaagtgc cattccacac aagaggaaaccgagggagca cggcttctga acagcggatc 240 tgaaaatgac tccacggaga tccagaatgaaaaggcggaa cctccgaaaa ccgaag atg 299 Met 1 agg ttc ctt ctc ctg aac aggttc acc ctg ctg ctc ctg ctc cta gtg 347 Arg Phe Leu Leu Leu Asn Arg PheThr Leu Leu Leu Leu Leu Leu Val 5 10 15 agc cct act cca gtt ctt cag gctcct acc aat ctc act gac tcc ggc 395 Ser Pro Thr Pro Val Leu Gln Ala ProThr Asn Leu Thr Asp Ser Gly 20 25 30 ctt gat cag gag cca ttc ctg tac ttggtt gga cgc aag aag ctt ctg 443 Leu Asp Gln Glu Pro Phe Leu Tyr Leu ValGly Arg Lys Lys Leu Leu 35 40 45 gat gct cag tac aag tgc tat gac cgg attcag cag ttg ccc cct tat 491 Asp Ala Gln Tyr Lys Cys Tyr Asp Arg Ile GlnGln Leu Pro Pro Tyr 50 55 60 65 gag gga gaa ggt cca tat tgc aac cga acttgg gat gga tgg atg tgc 539 Glu Gly Glu Gly Pro Tyr Cys Asn Arg Thr TrpAsp Gly Trp Met Cys 70 75 80 tgg gac gac act cca gct ggt gta atg tcc tatcag cac tgc cct gac 587 Trp Asp Asp Thr Pro Ala Gly Val Met Ser Tyr GlnHis Cys Pro Asp 85 90 95 tac ttt ccg gac ttt gac cca aca gaa aag gtt tcaaaa tac tgc gat 635 Tyr Phe Pro Asp Phe Asp Pro Thr Glu Lys Val Ser LysTyr Cys Asp 100 105 110 gag aat gga gag tgg ttt aga cac cct gac agc aaccga acc tgg tcc 683 Glu Asn Gly Glu Trp Phe Arg His Pro Asp Ser Asn ArgThr Trp Ser 115 120 125 aac tac act ctg tgc aat gcc ttc act cct gac aaactg cat aat gca 731 Asn Tyr Thr Leu Cys Asn Ala Phe Thr Pro Asp Lys LeuHis Asn Ala 130 135 140 145 tac gtt tct tat tac cta gca ctt gtg ggc cactcc atg tca att gct 779 Tyr Val Ser Tyr Tyr Leu Ala Leu Val Gly His SerMet Ser Ile Ala 150 155 160 gct ctg att gct tcc atg ggg atc ttc ttg tttttc aag aac ctt agc 827 Ala Leu Ile Ala Ser Met Gly Ile Phe Leu Phe PheLys Asn Leu Ser 165 170 175 tgc cag aga gtg act ctg cac aag aac atg ttcctc act tat atc ctg 875 Cys Gln Arg Val Thr Leu His Lys Asn Met Phe LeuThr Tyr Ile Leu 180 185 190 aac tct atc att atc atc atc cac ctg gtt gaggtt gtg ccc aat gga 923 Asn Ser Ile Ile Ile Ile Ile His Leu Val Glu ValVal Pro Asn Gly 195 200 205 gac ctg gtg cga cgg gat cct ata agt tgc aagatt ctg cac ttt ttc 971 Asp Leu Val Arg Arg Asp Pro Ile Ser Cys Lys IleLeu His Phe Phe 210 215 220 225 cat cag tac atg atg gct tgc aac tac ttctgg atg ctg tgt gag ggg 1019 His Gln Tyr Met Met Ala Cys Asn Tyr Phe TrpMet Leu Cys Glu Gly 230 235 240 atc tat ctt cac act ctg atc gtc atg gctgtg ttc acc gag gat caa 1067 Ile Tyr Leu His Thr Leu Ile Val Met Ala ValPhe Thr Glu Asp Gln 245 250 255 cgt ctg cgc tgg tac tat tta ctt ggc tggggg ttc cca ata gtg cca 1115 Arg Leu Arg Trp Tyr Tyr Leu Leu Gly Trp GlyPhe Pro Ile Val Pro 260 265 270 act att atc cat gcc att act cgt gcc gtctac tac aac gac aac tgt 1163 Thr Ile Ile His Ala Ile Thr Arg Ala Val TyrTyr Asn Asp Asn Cys 275 280 285 tgg ctg agt acg gag acc cac ttg ctt tacatc atc cat gga ccc gtc 1211 Trp Leu Ser Thr Glu Thr His Leu Leu Tyr IleIle His Gly Pro Val 290 295 300 305 atg gcg gct ctg gtg gtc aac ttc ttcttt ctg ctc aac att gtc cgt 1259 Met Ala Ala Leu Val Val Asn Phe Phe PheLeu Leu Asn Ile Val Arg 310 315 320 gtg ctt gtg acc aag atg agg caa acccat gaa gcc gag gcc tac atg 1307 Val Leu Val Thr Lys Met Arg Gln Thr HisGlu Ala Glu Ala Tyr Met 325 330 335 tac ctg aag gct gta aag gcc acc atggtc ctt gtg ccc ctg ctg ggg 1355 Tyr Leu Lys Ala Val Lys Ala Thr Met ValLeu Val Pro Leu Leu Gly 340 345 350 atc cag ttt gtt gtg ttt ccc tgg aggccc tcc aac aaa gtg ctt ggg 1403 Ile Gln Phe Val Val Phe Pro Trp Arg ProSer Asn Lys Val Leu Gly 355 360 365 aag atc tat gat tat ctc atg cac tctctg att cat ttc cag gga ttc 1451 Lys Ile Tyr Asp Tyr Leu Met His Ser LeuIle His Phe Gln Gly Phe 370 375 380 385 ttt gtc gcg act atc tac tgc ttctgt aac cat gag gtg caa gtg acc 1499 Phe Val Ala Thr Ile Tyr Cys Phe CysAsn His Glu Val Gln Val Thr 390 395 400 ctg aag cgt cag tgg gcg cag ttcaag atc cag tgg agc cat cgc tgg 1547 Leu Lys Arg Gln Trp Ala Gln Phe LysIle Gln Trp Ser His Arg Trp 405 410 415 ggt agg cgc cgg ccc acc aac cgagtg gtt agc gct cct cgt gct gta 1595 Gly Arg Arg Arg Pro Thr Asn Arg ValVal Ser Ala Pro Arg Ala Val 420 425 430 gcc ttt gca gaa cca ggt ggc cgcccc att tac atc tgc cat cag gaa 1643 Ala Phe Ala Glu Pro Gly Gly Arg ProIle Tyr Ile Cys His Gln Glu 435 440 445 cca agg aat cct cca gtc agc aacaac gaa ggc gaa gag ggt act gaa 1691 Pro Arg Asn Pro Pro Val Ser Asn AsnGlu Gly Glu Glu Gly Thr Glu 450 455 460 465 atg atc ccc atg aat gtc atccag caa gac tca tcc gct tga 1733 Met Ile Pro Met Asn Val Ile Gln Gln AspSer Ser Ala 470 475 atgcttgaat gtgaagcaac ccccccaaca ttgtgatccactgagccttc atttcctggg 1793 agaacgatag accatgcgtt tcaagtgatc cccatcctcccaggagctaa gcatatattt 1853 gtgaagatgt attaagtgaa tttgtccata gtgaatttgaagaacgttat tcttggtact 1913 attgctttgg gagtcaggct aggctctcag tgcaacttgtgaactccatt attcatctag 1973 gactgagatg acagtgttca taggaatgta gacaaggtatccaaaactgc cactaaattg 2033 acctagttca gataagggtg ctccatgtta atgttgagccatttgtacct ttgagaaact 2093 aaaatcactc tcaatgtttt taattttaac actggactttgaattagact atttctgtat 2153 ttggctacgg atctggtttt taatgttttt atttcagtcaattcctatat tgcacatttt 2213 ttcatccata caatgtcaac tgcacaaata acatgacctctggaagatgc tgtgtctttt 2273 ataacatgat ccacgtcacc aggcagaccc aaatactgtaaagaattgat ctgaatgttg 2333 agtgtgcttt ggtcactgac atttataaat tgggaggtcatcaagaacct atcactaaat 2393 ttttcacaaa actgaccccc ctcaaatgta attttccatcaaagagaaca ctctttaaag 2453 atagttttcc actttcctaa actacaggat ttataaagcaaatcattcca aggtttataa 2513 agcagattac ctcttgccct tgggtgctat ttagcagtgagggatacatt tgtttacgac 2573 tggtaattaa aagactccat tcaagtccat taactgccttccacccagct tcaaagcttg 2633 acaagatccc gtgttttcca ggaagactca gtgtggctaattacaaatca gtttctagtt 2693 gacctcttgt ttgcttctat tagcaaaaca aggagggaaaaaagcaaacc acaatgtaag 2753 gacttggagt ttaaccacat attagttcat cttaaattaaagacaagctt ctcaccaaaa 2813 ctcagtacca tatttccacg cctctcttta ctccccagaatgagatcttc caagatccac 2873 aaataaacca ataccattac caatttctga atctgcaactgcaatcaatt atcattatta 2933 atttgtatgc tgaatgagac gcatccttga gacccctaaaaatctcatct cctctttgtc 2993 atcttgtgtc actgcctttc agaggtgatt tagttgcgtaaaaacaaaag taacttgatt 3053 tgttctggtt acgtacttgg tgcacccaga gaaaattgtatttcgctagc agctgtggcc 3113 cttggatact gagagtctcc tttaccaaaa tgggagaattgaaaggaagg attttttttc 3173 caatcacagt gttacgtggt gatgttccca tgttttgtttacaaacattg aaatcagtgt 3233 atttcaggca gctctggtac aaatgtgata gtgtattgctgaagtgtttg agacgttatt 3293 gtgcttctgt agtaggggct gatgaaatca aactgacttatcatagcatt gcatgtaata 3353 cctaaattgt gtgaaacact tcttctgtgt acttgtataaattaatacaa gcatgtt 3410 26 478 PRT Rattus norvegicus 26 Met Arg Phe LeuLeu Leu Asn Arg Phe Thr Leu Leu Leu Leu Leu Leu 1 5 10 15 Val Ser ProThr Pro Val Leu Gln Ala Pro Thr Asn Leu Thr Asp Ser 20 25 30 Gly Leu AspGln Glu Pro Phe Leu Tyr Leu Val Gly Arg Lys Lys Leu 35 40 45 Leu Asp AlaGln Tyr Lys Cys Tyr Asp Arg Ile Gln Gln Leu Pro Pro 50 55 60 Tyr Glu GlyGlu Gly Pro Tyr Cys Asn Arg Thr Trp Asp Gly Trp Met 65 70 75 80 Cys TrpAsp Asp Thr Pro Ala Gly Val Met Ser Tyr Gln His Cys Pro 85 90 95 Asp TyrPhe Pro Asp Phe Asp Pro Thr Glu Lys Val Ser Lys Tyr Cys 100 105 110 AspGlu Asn Gly Glu Trp Phe Arg His Pro Asp Ser Asn Arg Thr Trp 115 120 125Ser Asn Tyr Thr Leu Cys Asn Ala Phe Thr Pro Asp Lys Leu His Asn 130 135140 Ala Tyr Val Ser Tyr Tyr Leu Ala Leu Val Gly His Ser Met Ser Ile 145150 155 160 Ala Ala Leu Ile Ala Ser Met Gly Ile Phe Leu Phe Phe Lys AsnLeu 165 170 175 Ser Cys Gln Arg Val Thr Leu His Lys Asn Met Phe Leu ThrTyr Ile 180 185 190 Leu Asn Ser Ile Ile Ile Ile Ile His Leu Val Glu ValVal Pro Asn 195 200 205 Gly Asp Leu Val Arg Arg Asp Pro Ile Ser Cys LysIle Leu His Phe 210 215 220 Phe His Gln Tyr Met Met Ala Cys Asn Tyr PheTrp Met Leu Cys Glu 225 230 235 240 Gly Ile Tyr Leu His Thr Leu Ile ValMet Ala Val Phe Thr Glu Asp 245 250 255 Gln Arg Leu Arg Trp Tyr Tyr LeuLeu Gly Trp Gly Phe Pro Ile Val 260 265 270 Pro Thr Ile Ile His Ala IleThr Arg Ala Val Tyr Tyr Asn Asp Asn 275 280 285 Cys Trp Leu Ser Thr GluThr His Leu Leu Tyr Ile Ile His Gly Pro 290 295 300 Val Met Ala Ala LeuVal Val Asn Phe Phe Phe Leu Leu Asn Ile Val 305 310 315 320 Arg Val LeuVal Thr Lys Met Arg Gln Thr His Glu Ala Glu Ala Tyr 325 330 335 Met TyrLeu Lys Ala Val Lys Ala Thr Met Val Leu Val Pro Leu Leu 340 345 350 GlyIle Gln Phe Val Val Phe Pro Trp Arg Pro Ser Asn Lys Val Leu 355 360 365Gly Lys Ile Tyr Asp Tyr Leu Met His Ser Leu Ile His Phe Gln Gly 370 375380 Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn His Glu Val Gln Val 385390 395 400 Thr Leu Lys Arg Gln Trp Ala Gln Phe Lys Ile Gln Trp Ser HisArg 405 410 415 Trp Gly Arg Arg Arg Pro Thr Asn Arg Val Val Ser Ala ProArg Ala 420 425 430 Val Ala Phe Ala Glu Pro Gly Gly Arg Pro Ile Tyr IleCys His Gln 435 440 445 Glu Pro Arg Asn Pro Pro Val Ser Asn Asn Glu GlyGlu Glu Gly Thr 450 455 460 Glu Met Ile Pro Met Asn Val Ile Gln Gln AspSer Ser Ala 465 470 475 27 3382 DNA Rattus norvegicus CDS (242)..(1681)27 ctgcagcttg cagacaactc ctggttggag aggtgcttct gcacctcact ctgaggttgg 60caccccctgc ccagtgaagt ctgagttcct gagacatcca gctagagaat tcctgcgtcc 120acctaaggta agtgccattc cacacaagag gaaaccgagg gagcacggct tctgaacagc 180ggatctgaaa atgactccac ggagatccag aatgaaaagg cggaacctcc gaaaaccgaa 240 gatg agg ttc ctt ctc ctg aac agg ttc acc ctg ctg ctc ctg ctc cta 289 MetArg Phe Leu Leu Leu Asn Arg Phe Thr Leu Leu Leu Leu Leu Leu 1 5 10 15gtg agc cct act cca gtt ctt cag gct cct acc aat ctc act gac tcc 337 ValSer Pro Thr Pro Val Leu Gln Ala Pro Thr Asn Leu Thr Asp Ser 20 25 30 ggcctt gat cag gag cca ttc ctg tac ttg gtt gga cgc aag aag ctt 385 Gly LeuAsp Gln Glu Pro Phe Leu Tyr Leu Val Gly Arg Lys Lys Leu 35 40 45 ctg gatgct cag tac aag tgc tat gac cgg att cag cag ttg ccc cct 433 Leu Asp AlaGln Tyr Lys Cys Tyr Asp Arg Ile Gln Gln Leu Pro Pro 50 55 60 tat gag ggagaa ggt cca tat tgc aac cga act tgg gat gga tgg atg 481 Tyr Glu Gly GluGly Pro Tyr Cys Asn Arg Thr Trp Asp Gly Trp Met 65 70 75 80 tgc tgg gacgac act cca gct ggt gta atg tcc tat cag cac tgc cct 529 Cys Trp Asp AspThr Pro Ala Gly Val Met Ser Tyr Gln His Cys Pro 85 90 95 gac tac ttt ccggac ttt gac cca aca gaa aag gtt tca aaa tac tgc 577 Asp Tyr Phe Pro AspPhe Asp Pro Thr Glu Lys Val Ser Lys Tyr Cys 100 105 110 gat gaa aat ggagag tgg ttt aga cac cct gac agc aac cga acc tgg 625 Asp Glu Asn Gly GluTrp Phe Arg His Pro Asp Ser Asn Arg Thr Trp 115 120 125 tcc aac tac actctg tgc aat gcc ttc act cct gac aaa ctg cat aat 673 Ser Asn Tyr Thr LeuCys Asn Ala Phe Thr Pro Asp Lys Leu His Asn 130 135 140 gca tac gtt ctttat tac cta gca ctt gtg ggc cac tcc atg tca att 721 Ala Tyr Val Leu TyrTyr Leu Ala Leu Val Gly His Ser Met Ser Ile 145 150 155 160 gct gct ctgatt gct tcc atg ggg atc ttc ttg ttt ttc aag aac ctt 769 Ala Ala Leu IleAla Ser Met Gly Ile Phe Leu Phe Phe Lys Asn Leu 165 170 175 agc tgc cagaga gtg act ctg cac aag aac atg ttc ctc act tat atc 817 Ser Cys Gln ArgVal Thr Leu His Lys Asn Met Phe Leu Thr Tyr Ile 180 185 190 ctg aac tctatc att atc atc atc cac ctg gtt gag gtt gtg ccc aat 865 Leu Asn Ser IleIle Ile Ile Ile His Leu Val Glu Val Val Pro Asn 195 200 205 gga gac ctggtg cga cgg gat cct ata agt tgc aag att ctg cac ttt 913 Gly Asp Leu ValArg Arg Asp Pro Ile Ser Cys Lys Ile Leu His Phe 210 215 220 ttc cat cagtac atg atg gct tgc aac tac ttc tgg atg ctg tgt gag 961 Phe His Gln TyrMet Met Ala Cys Asn Tyr Phe Trp Met Leu Cys Glu 225 230 235 240 ggg atctat ctt cac act ctg atc gtc atg gct gtg ttc acc gag gat 1009 Gly Ile TyrLeu His Thr Leu Ile Val Met Ala Val Phe Thr Glu Asp 245 250 255 caa cgtctg cgc tgg tac tat tta ctt ggc tgg ggg ttc cca ata gtg 1057 Gln Arg LeuArg Trp Tyr Tyr Leu Leu Gly Trp Gly Phe Pro Ile Val 260 265 270 cca actatt atc cat gcc att act cgt gcc gtc tac tac aac gac aac 1105 Pro Thr IleIle His Ala Ile Thr Arg Ala Val Tyr Tyr Asn Asp Asn 275 280 285 tgt tggctg agt acg gag acc cac ttg ctt tac atc atc cat gga ccc 1153 Cys Trp LeuSer Thr Glu Thr His Leu Leu Tyr Ile Ile His Gly Pro 290 295 300 gtc atggcg gct ctg gtg gtc aac ttc ttc ttt ctg ctc aac att gtc 1201 Val Met AlaAla Leu Val Val Asn Phe Phe Phe Leu Leu Asn Ile Val 305 310 315 320 cgtgtg ctt gtg acc aag atg agg caa acc cat gaa gcc gag gcc tac 1249 Arg ValLeu Val Thr Lys Met Arg Gln Thr His Glu Ala Glu Ala Tyr 325 330 335 atgtac ctg aag gct gta aag gcc acc atg gtc ctt gtg ccc ctg ctg 1297 Met TyrLeu Lys Ala Val Lys Ala Thr Met Val Leu Val Pro Leu Leu 340 345 350 gggatc cag ttt gtt gtg ttt ccc tgg agg ccc tcc aac aaa gtg ctt 1345 Gly IleGln Phe Val Val Phe Pro Trp Arg Pro Ser Asn Lys Val Leu 355 360 365 gggaag atc tat gat tat ctc atg cac tct ctg att cat ttc cag gga 1393 Gly LysIle Tyr Asp Tyr Leu Met His Ser Leu Ile His Phe Gln Gly 370 375 380 ttcttt gtc gcg act atc tac tgc ttc tgt aac cat gag gtg caa gtg 1441 Phe PheVal Ala Thr Ile Tyr Cys Phe Cys Asn His Glu Val Gln Val 385 390 395 400acc ctg aag cgt cag tgg gcg cag ttc aag atc cag tgg agc cat cgc 1489 ThrLeu Lys Arg Gln Trp Ala Gln Phe Lys Ile Gln Trp Ser His Arg 405 410 415tgg ggt agg cgc cgc cgc ccc acc aac cga gtg gtt agc gct cct cgt 1537 TrpGly Arg Arg Arg Arg Pro Thr Asn Arg Val Val Ser Ala Pro Arg 420 425 430gct gta gcc ttt gca gaa cca ggt ggc ctc ccc att tac atc tgc cat 1585 AlaVal Ala Phe Ala Glu Pro Gly Gly Leu Pro Ile Tyr Ile Cys His 435 440 445cag gaa cca agg aat cct cca gtc agc aac aac gaa ggc gaa gag ggt 1633 GlnGlu Pro Arg Asn Pro Pro Val Ser Asn Asn Glu Gly Glu Glu Gly 450 455 460act gaa atg atc ccc atg aat gtc atc cag caa gac tca tcc gct tga 1681 ThrGlu Met Ile Pro Met Asn Val Ile Gln Gln Asp Ser Ser Ala 465 470 475atgcttgaat gtgaagcaac cccccaacat tgtgatccac tgagccttca tttcctggga 1741gaacgataga ccatgcgttt caagtgatcc ccatcctccc aggagctaag catatcattt 1801gtgaagatgt attaagtgaa tttgtccata gtgaatttga agaacgttat tcttggtact 1861attgctttgg gagtcaggct aggctctcag tgcaacttgt gaactccatt attcatctag 1921gactgagatg acagtgttca taggaatgta gacaaggtat ccaaaactgc cactaaattg 1981acctagttca gataagggtg ctccatgtta atcttgagcc atttgtacct ttgagaaact 2041aaaatcactc tcaatgtttt taattttaac actggacttt gaattagact atttctgtat 2101ttggctacgg atctggtttt taatgttttt atttcagtca attcctatat tgcacatttt 2161ttcatccata caatgtcaac tgcacaaata acatgacctc tggaagatgc tgtgtctttt 2221ataacatgat ccacgtcacc aggcagaccc aaatactgta aagaattgat ctgaatgttg 2281agtgtgcttt ggtcactgac atttataaat tgggaggtca tcaagaacct atcactaaat 2341ttttcacaaa actgaccccc ctcaaatgta attttccatc aaagagaaca ctctttaaag 2401atagttttcc actttcctaa actacaggat ttataaagca aatcattcca aggtttataa 2461agcagattac ctcttgccct tgggtgctat ttagcagtga gggatagatt tgtttacgac 2521tggtaattaa aagactccat tcaagtccat taactgcctt ccacccagct tcaaagcttg 2581acaagatccc gtgttttcca ggaagactca gtgtggctaa ttacaaatca gtttctagtt 2641gacctcttgt ttgcttctat tagcaaaaca aggagggaaa aaagcaaacc acaatgtaag 2701gacttggagt ttaaccacat attagttcat cttaaattaa agacaagctt ctcaccaaaa 2761ctcagtacca tatttccacg cctctcttta ctccccagaa tgagatcttc caagatccac 2821aaataaacca ataccattac caatttctga atctgcaact gcaatcaatt atcattatta 2881atttgtatgc tgaatgagac gcatccttga gacccttaaa aatctcatct cctctttgtc 2941atcttgtgtc actgcctttc agaggtgatt tagttgcgta aaaacaaaag taacttgatt 3001tgttctggtt acgtacttgg tgcacccaga gaaaattgta tttcgctagc agctgtggcc 3061cttggatact gagagtctcc tttaccaaaa tgggagaatt gaaaggaagg attttttttc 3121caatcacagt gttacgtggt gatgttccca tgttttgttt acaaacattg aaatcagtgt 3181atttcaggca gctctggtac aaatgtgata gtgtattgct gaagtgtttg agacgttatt 3241gtgcttctgt agtaggggct gatgaaatca aactgactta tcatagcatt gcatgtaata 3301cctaaattgt gtgaaacact tcttctgtgt acttgtataa attaatacaa gcatgttgaa 3361aaggcaaaaa aaaaaaaaaa a 3382 28 479 PRT Rattus norvegicus 28 Met Arg PheLeu Leu Leu Asn Arg Phe Thr Leu Leu Leu Leu Leu Leu 1 5 10 15 Val SerPro Thr Pro Val Leu Gln Ala Pro Thr Asn Leu Thr Asp Ser 20 25 30 Gly LeuAsp Gln Glu Pro Phe Leu Tyr Leu Val Gly Arg Lys Lys Leu 35 40 45 Leu AspAla Gln Tyr Lys Cys Tyr Asp Arg Ile Gln Gln Leu Pro Pro 50 55 60 Tyr GluGly Glu Gly Pro Tyr Cys Asn Arg Thr Trp Asp Gly Trp Met 65 70 75 80 CysTrp Asp Asp Thr Pro Ala Gly Val Met Ser Tyr Gln His Cys Pro 85 90 95 AspTyr Phe Pro Asp Phe Asp Pro Thr Glu Lys Val Ser Lys Tyr Cys 100 105 110Asp Glu Asn Gly Glu Trp Phe Arg His Pro Asp Ser Asn Arg Thr Trp 115 120125 Ser Asn Tyr Thr Leu Cys Asn Ala Phe Thr Pro Asp Lys Leu His Asn 130135 140 Ala Tyr Val Leu Tyr Tyr Leu Ala Leu Val Gly His Ser Met Ser Ile145 150 155 160 Ala Ala Leu Ile Ala Ser Met Gly Ile Phe Leu Phe Phe LysAsn Leu 165 170 175 Ser Cys Gln Arg Val Thr Leu His Lys Asn Met Phe LeuThr Tyr Ile 180 185 190 Leu Asn Ser Ile Ile Ile Ile Ile His Leu Val GluVal Val Pro Asn 195 200 205 Gly Asp Leu Val Arg Arg Asp Pro Ile Ser CysLys Ile Leu His Phe 210 215 220 Phe His Gln Tyr Met Met Ala Cys Asn TyrPhe Trp Met Leu Cys Glu 225 230 235 240 Gly Ile Tyr Leu His Thr Leu IleVal Met Ala Val Phe Thr Glu Asp 245 250 255 Gln Arg Leu Arg Trp Tyr TyrLeu Leu Gly Trp Gly Phe Pro Ile Val 260 265 270 Pro Thr Ile Ile His AlaIle Thr Arg Ala Val Tyr Tyr Asn Asp Asn 275 280 285 Cys Trp Leu Ser ThrGlu Thr His Leu Leu Tyr Ile Ile His Gly Pro 290 295 300 Val Met Ala AlaLeu Val Val Asn Phe Phe Phe Leu Leu Asn Ile Val 305 310 315 320 Arg ValLeu Val Thr Lys Met Arg Gln Thr His Glu Ala Glu Ala Tyr 325 330 335 MetTyr Leu Lys Ala Val Lys Ala Thr Met Val Leu Val Pro Leu Leu 340 345 350Gly Ile Gln Phe Val Val Phe Pro Trp Arg Pro Ser Asn Lys Val Leu 355 360365 Gly Lys Ile Tyr Asp Tyr Leu Met His Ser Leu Ile His Phe Gln Gly 370375 380 Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn His Glu Val Gln Val385 390 395 400 Thr Leu Lys Arg Gln Trp Ala Gln Phe Lys Ile Gln Trp SerHis Arg 405 410 415 Trp Gly Arg Arg Arg Arg Pro Thr Asn Arg Val Val SerAla Pro Arg 420 425 430 Ala Val Ala Phe Ala Glu Pro Gly Gly Leu Pro IleTyr Ile Cys His 435 440 445 Gln Glu Pro Arg Asn Pro Pro Val Ser Asn AsnGlu Gly Glu Glu Gly 450 455 460 Thr Glu Met Ile Pro Met Asn Val Ile GlnGln Asp Ser Ser Ala 465 470 475 29 3282 DNA Rattus norvegicus CDS(73)..(1620) 29 cggcacgagg cggatctgaa aatgactcct aggagatcca gaatgaaaaggcggaacctc 60 cgaaaaccga ag atg agg ttc ctt ctc ctg aac agg ttc acc ctgctg ctc 111 Met Arg Phe Leu Leu Leu Asn Arg Phe Thr Leu Leu Leu 1 5 10ctg ctc cta gtg agc cct act cca gtt ctt cag gct cct acc aat ctc 159 LeuLeu Leu Val Ser Pro Thr Pro Val Leu Gln Ala Pro Thr Asn Leu 15 20 25 actgac tcc ggc ctt gat cag gag cca ttc ctg tac ttg gtt gga cgc 207 Thr AspSer Gly Leu Asp Gln Glu Pro Phe Leu Tyr Leu Val Gly Arg 30 35 40 45 aagaag ctt ctg gat gct cag tac aag tgc tat gac cgg att cag cag 255 Lys LysLeu Leu Asp Ala Gln Tyr Lys Cys Tyr Asp Arg Ile Gln Gln 50 55 60 ttg ccccct tat gag gga gaa ggt cca tat tgc aac cga act tgg gat 303 Leu Pro ProTyr Glu Gly Glu Gly Pro Tyr Cys Asn Arg Thr Trp Asp 65 70 75 gga tgg atgtgc tgg gac gac act cca gct ggt gta atg tcc tat cag 351 Gly Trp Met CysTrp Asp Asp Thr Pro Ala Gly Val Met Ser Tyr Gln 80 85 90 cac tgc cct gactac ttt ccg gac ttt gac cca aca gaa aag gtt tca 399 His Cys Pro Asp TyrPhe Pro Asp Phe Asp Pro Thr Glu Lys Val Ser 95 100 105 aaa tac tgc gatgag aat gga gag tgg ttt aga cac cct gac agc aac 447 Lys Tyr Cys Asp GluAsn Gly Glu Trp Phe Arg His Pro Asp Ser Asn 110 115 120 125 cga acc tggtcc aac tac act ctg tgc aat gcc ttc act cct gac aaa 495 Arg Thr Trp SerAsn Tyr Thr Leu Cys Asn Ala Phe Thr Pro Asp Lys 130 135 140 ctg cat aatgca tac gtt tct tat tac cta gca ctt gtg ggc cac tcc 543 Leu His Asn AlaTyr Val Ser Tyr Tyr Leu Ala Leu Val Gly His Ser 145 150 155 atg tca attgct gct ctg att gct tcc atg ggg atc ttc ttg ttt ttc 591 Met Ser Ile AlaAla Leu Ile Ala Ser Met Gly Ile Phe Leu Phe Phe 160 165 170 aag aac cttagc tgc cag aga gtg act ctg cac aag aac atg ttc ctc 639 Lys Asn Leu SerCys Gln Arg Val Thr Leu His Lys Asn Met Phe Leu 175 180 185 act tat atcctg aac tct atc att atc atc atc cac ctg gtt gag gtt 687 Thr Tyr Ile LeuAsn Ser Ile Ile Ile Ile Ile His Leu Val Glu Val 190 195 200 205 gtg cccaat gga gac ctg gtg cga cgg gat cct atg cat att ttt cat 735 Val Pro AsnGly Asp Leu Val Arg Arg Asp Pro Met His Ile Phe His 210 215 220 cat aacaca tat atg tgg aca atg cag tgg gaa ctg tca cca ccc tta 783 His Asn ThrTyr Met Trp Thr Met Gln Trp Glu Leu Ser Pro Pro Leu 225 230 235 ccc ctgagt gca cac gag gga aag atg gac cct cat gac agt gaa gtg 831 Pro Leu SerAla His Glu Gly Lys Met Asp Pro His Asp Ser Glu Val 240 245 250 ata agttgc aag att ctg cac ttt ttc cat cag tac atg atg gct tgc 879 Ile Ser CysLys Ile Leu His Phe Phe His Gln Tyr Met Met Ala Cys 255 260 265 aac tacttc tgg atg ctg tgt gag ggg atc tat ctt cac act ctg atc 927 Asn Tyr PheTrp Met Leu Cys Glu Gly Ile Tyr Leu His Thr Leu Ile 270 275 280 285 gtcatg gct gtg ttc acc gag gat caa cgt ctg cgc tgg tac tat tta 975 Val MetAla Val Phe Thr Glu Asp Gln Arg Leu Arg Trp Tyr Tyr Leu 290 295 300 cttggc tgg ggg ttc cca ata gtg cca act att atc cat gcc att act 1023 Leu GlyTrp Gly Phe Pro Ile Val Pro Thr Ile Ile His Ala Ile Thr 305 310 315 cgtgcc gtc tac tac aac gac aac tgt tgg ctg agt acg gag acc cac 1071 Arg AlaVal Tyr Tyr Asn Asp Asn Cys Trp Leu Ser Thr Glu Thr His 320 325 330 ttgctt tac atc atc cat gga ccc gtc atg gcg gct ctg gtg gtc aac 1119 Leu LeuTyr Ile Ile His Gly Pro Val Met Ala Ala Leu Val Val Asn 335 340 345 ttcttc ttt ctg ctc aac att gtc cgt gtg ctt gtg acc aag atg agg 1167 Phe PhePhe Leu Leu Asn Ile Val Arg Val Leu Val Thr Lys Met Arg 350 355 360 365caa acc cat gaa gcc gag gcc tac atg tac ctg aag gct gta aag gcc 1215 GlnThr His Glu Ala Glu Ala Tyr Met Tyr Leu Lys Ala Val Lys Ala 370 375 380acc atg gtc ctt gtg ccc ctg ctg ggg atc cag ttt gtt gtg ttt ccc 1263 ThrMet Val Leu Val Pro Leu Leu Gly Ile Gln Phe Val Val Phe Pro 385 390 395tgg agg ccc tcc aac aaa gtg ctt ggg aag atc tat gat tat ctc atg 1311 TrpArg Pro Ser Asn Lys Val Leu Gly Lys Ile Tyr Asp Tyr Leu Met 400 405 410cac tct ctg att cat ttc cag gga ttc ttt gtc gcg act atc tac tgc 1359 HisSer Leu Ile His Phe Gln Gly Phe Phe Val Ala Thr Ile Tyr Cys 415 420 425ttc tgt aac cat gag gtg caa gtg acc ctg aag cgt cag tgg gcg cag 1407 PheCys Asn His Glu Val Gln Val Thr Leu Lys Arg Gln Trp Ala Gln 430 435 440445 ttc aag atc cag tgg agc cat cgc tgg ggt agg cgc cgg ccc acc aac 1455Phe Lys Ile Gln Trp Ser His Arg Trp Gly Arg Arg Arg Pro Thr Asn 450 455460 cga gtg gtt agc gct cct cgt gct gta gcc ttt gca gaa cca ggt ggc 1503Arg Val Val Ser Ala Pro Arg Ala Val Ala Phe Ala Glu Pro Gly Gly 465 470475 cgc ccc att tac atc tgc cat cag gaa cca agg aat cct cca gtc agc 1551Arg Pro Ile Tyr Ile Cys His Gln Glu Pro Arg Asn Pro Pro Val Ser 480 485490 aac aac gaa ggc gaa gag ggt act gaa atg atc ccc atg aat gtc atc 1599Asn Asn Glu Gly Glu Glu Gly Thr Glu Met Ile Pro Met Asn Val Ile 495 500505 cag caa gac tca tcc gct tga atgcttgaat gtgaagcaac ccccccaaca 1650Gln Gln Asp Ser Ser Ala 510 515 ttgtgatcca ctgagccttc atttcctgggagaacgatag accatgcgtt tcaagtgatc 1710 cccatcctcc caggagctaa gcatatatttgtgaagatgt attaagtgaa tttgtccata 1770 gtgaatttga agaacgttat tcttggtactattgctttgg gagtcaggct aggctctcag 1830 tgcaacttgt gaactccatt attcatctaggactgagatg acagtgttca taggaatgta 1890 gacaaggtat ccaaaactgc cactaaattgacctagttca gataagggtg ctccatgtta 1950 atgttgagcc atttgtacct ttgagaaactaaaatcactc tcaatgtttt taattttaac 2010 actggacttt gaattagact atttctgtatttggctacgg atctggtttt taatgttttt 2070 atttcagtca attcctatat tgcacattttttcatccata caatgtcaac tgcacaaata 2130 acatgacctc tggaagatgc tgtgtcttttataacatgat ccacgtcacc aggcagaccc 2190 aaatactgta aagaattgat ctgaatgttgagtgtgcttt ggtcactgac atttataaat 2250 tgggaggtca tcaagaacct atcactaaatttttcacaaa actgaccccc ctcaaatgta 2310 attttccatc aaagagaaca ctctttaaagatagttttcc actttcctaa actacaggat 2370 ttataaagca aatcattcca aggtttataaagcagattac ctcttgccct tgggtgctat 2430 ttagcagtga gggatacatt tgtttacgactggtaattaa aagactccat tcaagtccat 2490 taactgcctt ccacccagct tcaaagcttgacaagatccc gtgttttcca ggaagactca 2550 gtgtggctaa ttacaaatca gtttctagttgacctcttgt ttgcttctat tagcaaaaca 2610 aggagggaaa aaagcaaacc acaatgtaaggacttggagt ttaaccacat attagttcat 2670 cttaaattaa agacaagctt ctcaccaaaactcagtacca tatttccacg cctctcttta 2730 ctccccagaa tgagatcttc caagatccacaaataaacca ataccattac caatttctga 2790 atctgcaact gcaatcaatt atcattattaatttgtatgc tgaatgagac gcatccttga 2850 gacccctaaa aatctcatct cctctttgtcatcttgtgtc actgcctttc agaggtgatt 2910 tagttgcgta aaaacaaaag taacttgatttgttctggtt acgtacttgg tgcacccaga 2970 gaaaattgta tttcgctagc agctgtggcccttggatact gagagtctcc tttaccaaaa 3030 tgggagaatt gaaaggaagg atttttttttccaatcacag tgttacgtgg tgatgttccc 3090 atgttttgtt tacaaacatt gaaatcagtgtatttcaggc agctctggta caaatgtgat 3150 agtgtattgc tgaagtgttt gagacgttattgtgcttctg tagtaggggc tgatgaaatc 3210 aaactgactt atcatagcat tgcatgtaatacctaaattg tgtgaaacac ttcttctgtg 3270 tgtagtcgtg cc 3282 30 515 PRTRattus norvegicus 30 Met Arg Phe Leu Leu Leu Asn Arg Phe Thr Leu Leu LeuLeu Leu Leu 1 5 10 15 Val Ser Pro Thr Pro Val Leu Gln Ala Pro Thr AsnLeu Thr Asp Ser 20 25 30 Gly Leu Asp Gln Glu Pro Phe Leu Tyr Leu Val GlyArg Lys Lys Leu 35 40 45 Leu Asp Ala Gln Tyr Lys Cys Tyr Asp Arg Ile GlnGln Leu Pro Pro 50 55 60 Tyr Glu Gly Glu Gly Pro Tyr Cys Asn Arg Thr TrpAsp Gly Trp Met 65 70 75 80 Cys Trp Asp Asp Thr Pro Ala Gly Val Met SerTyr Gln His Cys Pro 85 90 95 Asp Tyr Phe Pro Asp Phe Asp Pro Thr Glu LysVal Ser Lys Tyr Cys 100 105 110 Asp Glu Asn Gly Glu Trp Phe Arg His ProAsp Ser Asn Arg Thr Trp 115 120 125 Ser Asn Tyr Thr Leu Cys Asn Ala PheThr Pro Asp Lys Leu His Asn 130 135 140 Ala Tyr Val Ser Tyr Tyr Leu AlaLeu Val Gly His Ser Met Ser Ile 145 150 155 160 Ala Ala Leu Ile Ala SerMet Gly Ile Phe Leu Phe Phe Lys Asn Leu 165 170 175 Ser Cys Gln Arg ValThr Leu His Lys Asn Met Phe Leu Thr Tyr Ile 180 185 190 Leu Asn Ser IleIle Ile Ile Ile His Leu Val Glu Val Val Pro Asn 195 200 205 Gly Asp LeuVal Arg Arg Asp Pro Met His Ile Phe His His Asn Thr 210 215 220 Tyr MetTrp Thr Met Gln Trp Glu Leu Ser Pro Pro Leu Pro Leu Ser 225 230 235 240Ala His Glu Gly Lys Met Asp Pro His Asp Ser Glu Val Ile Ser Cys 245 250255 Lys Ile Leu His Phe Phe His Gln Tyr Met Met Ala Cys Asn Tyr Phe 260265 270 Trp Met Leu Cys Glu Gly Ile Tyr Leu His Thr Leu Ile Val Met Ala275 280 285 Val Phe Thr Glu Asp Gln Arg Leu Arg Trp Tyr Tyr Leu Leu GlyTrp 290 295 300 Gly Phe Pro Ile Val Pro Thr Ile Ile His Ala Ile Thr ArgAla Val 305 310 315 320 Tyr Tyr Asn Asp Asn Cys Trp Leu Ser Thr Glu ThrHis Leu Leu Tyr 325 330 335 Ile Ile His Gly Pro Val Met Ala Ala Leu ValVal Asn Phe Phe Phe 340 345 350 Leu Leu Asn Ile Val Arg Val Leu Val ThrLys Met Arg Gln Thr His 355 360 365 Glu Ala Glu Ala Tyr Met Tyr Leu LysAla Val Lys Ala Thr Met Val 370 375 380 Leu Val Pro Leu Leu Gly Ile GlnPhe Val Val Phe Pro Trp Arg Pro 385 390 395 400 Ser Asn Lys Val Leu GlyLys Ile Tyr Asp Tyr Leu Met His Ser Leu 405 410 415 Ile His Phe Gln GlyPhe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn 420 425 430 His Glu Val GlnVal Thr Leu Lys Arg Gln Trp Ala Gln Phe Lys Ile 435 440 445 Gln Trp SerHis Arg Trp Gly Arg Arg Arg Pro Thr Asn Arg Val Val 450 455 460 Ser AlaPro Arg Ala Val Ala Phe Ala Glu Pro Gly Gly Arg Pro Ile 465 470 475 480Tyr Ile Cys His Gln Glu Pro Arg Asn Pro Pro Val Ser Asn Asn Glu 485 490495 Gly Glu Glu Gly Thr Glu Met Ile Pro Met Asn Val Ile Gln Gln Asp 500505 510 Ser Ser Ala 515 31 1808 DNA Rattus norvegicus CDS (242)..(1792)31 ctgcagcttg cagacaactc ctggttggag aggtgcttct gcacctcact ctgaggttgg 60caccccctgc ccagtgaagt ctgagttcct gagacatcca gctagagaat tcctgcgtcc 120acctaaggta agtgccattc cacacaagag gaaaccgagg gagcacggct tctgaacagc 180ggatctgaaa atgactccac ggagatccag aatgaaaagg cggaacctcc gaaaaccgaa 240 gatg agg ttc ctt ctc ctg aac agg ttc acc ctg ctg ctc ctg ctc cta 289 MetArg Phe Leu Leu Leu Asn Arg Phe Thr Leu Leu Leu Leu Leu Leu 1 5 10 15gtg agc cct act cca gtt ctt cag gct cct acc aat ctc act gac tcc 337 ValSer Pro Thr Pro Val Leu Gln Ala Pro Thr Asn Leu Thr Asp Ser 20 25 30 ggcctt gat cag gag cca ttc ctg tac ttg gtt gga cgc aag aag ctt 385 Gly LeuAsp Gln Glu Pro Phe Leu Tyr Leu Val Gly Arg Lys Lys Leu 35 40 45 ctg gatgct cag tac aag tgc tat gac cgg att cag cag ttg ccc cct 433 Leu Asp AlaGln Tyr Lys Cys Tyr Asp Arg Ile Gln Gln Leu Pro Pro 50 55 60 tat gag ggagaa ggt cca tat tgc aac cga act tgg gat gga tgg atg 481 Tyr Glu Gly GluGly Pro Tyr Cys Asn Arg Thr Trp Asp Gly Trp Met 65 70 75 80 tgc tgg gacgac act cca gct ggt gta atg tcc tat cag cac tgc cct 529 Cys Trp Asp AspThr Pro Ala Gly Val Met Ser Tyr Gln His Cys Pro 85 90 95 gac tac ttt ccggac ttt gac cca aca gaa aag gtt tca aaa tac tgc 577 Asp Tyr Phe Pro AspPhe Asp Pro Thr Glu Lys Val Ser Lys Tyr Cys 100 105 110 gat gaa aat ggagag tgg ttt aga cac cct gac agc aac cga acc tgg 625 Asp Glu Asn Gly GluTrp Phe Arg His Pro Asp Ser Asn Arg Thr Trp 115 120 125 tcc aac tac actctg tgc aat gcc ttc act cct gac aaa ctg cat aat 673 Ser Asn Tyr Thr LeuCys Asn Ala Phe Thr Pro Asp Lys Leu His Asn 130 135 140 gca tac gtt ctttat tac cta gca ctt gtg ggc cac tcc atg tca att 721 Ala Tyr Val Leu TyrTyr Leu Ala Leu Val Gly His Ser Met Ser Ile 145 150 155 160 gct gct ctgatt gct tcc atg ggg atc ttc ttg ttt ttc aag aac ctt 769 Ala Ala Leu IleAla Ser Met Gly Ile Phe Leu Phe Phe Lys Asn Leu 165 170 175 agc tgc cagaga gtg act ctg cac aag aac atg ttc ctc act tat atc 817 Ser Cys Gln ArgVal Thr Leu His Lys Asn Met Phe Leu Thr Tyr Ile 180 185 190 ctg aac tctatc att atc atc atc cac ctg gtt gag gtt gtg ccc aat 865 Leu Asn Ser IleIle Ile Ile Ile His Leu Val Glu Val Val Pro Asn 195 200 205 gga gac ctggtg cga cgg gat cct atg cat att ttt cat cat aac aca 913 Gly Asp Leu ValArg Arg Asp Pro Met His Ile Phe His His Asn Thr 210 215 220 tat atg tggaca atg cag tgg gaa ctg tca cca ccc tta ccc ctg agt 961 Tyr Met Trp ThrMet Gln Trp Glu Leu Ser Pro Pro Leu Pro Leu Ser 225 230 235 240 gca cacgag gga aag atg gac cct cat gac agt gaa gtg ata agt tgc 1009 Ala His GluGly Lys Met Asp Pro His Asp Ser Glu Val Ile Ser Cys 245 250 255 aag attctg cac ttt ttc cat cag tac atg atg gct tgc aac tac ttc 1057 Lys Ile LeuHis Phe Phe His Gln Tyr Met Met Ala Cys Asn Tyr Phe 260 265 270 tgg atgctg tgt gag ggg atc tat ctt cac act ctg atc gtc atg gct 1105 Trp Met LeuCys Glu Gly Ile Tyr Leu His Thr Leu Ile Val Met Ala 275 280 285 gtg ttcacc gag gat caa cgt ctg cgc tgg tac tat tta ctt ggc tgg 1153 Val Phe ThrGlu Asp Gln Arg Leu Arg Trp Tyr Tyr Leu Leu Gly Trp 290 295 300 ggg ttccca ata gtg cca act att atc cat gcc att act cgt gcc gtc 1201 Gly Phe ProIle Val Pro Thr Ile Ile His Ala Ile Thr Arg Ala Val 305 310 315 320 tattac aac gac aac tgt tgg ctg agt acg gag acc cac ttg ctt tac 1249 Tyr TyrAsn Asp Asn Cys Trp Leu Ser Thr Glu Thr His Leu Leu Tyr 325 330 335 atcatc cat gga ccc gtc atg gcg gct ctg gtg gtc aac ttc ttc ttc 1297 Ile IleHis Gly Pro Val Met Ala Ala Leu Val Val Asn Phe Phe Phe 340 345 350 ctgctc aac att gtc cgt gtg ctt gtg acc aag atg agg caa acc cat 1345 Leu LeuAsn Ile Val Arg Val Leu Val Thr Lys Met Arg Gln Thr His 355 360 365 gaagcc gag gcc tac atg tac ctg aag gct gta aag gcc acc atg gtc 1393 Glu AlaGlu Ala Tyr Met Tyr Leu Lys Ala Val Lys Ala Thr Met Val 370 375 380 cttgtg ccc ctg ctg ggg atc cag ttt gtt gtg ttt ccc tgg agg ccc 1441 Leu ValPro Leu Leu Gly Ile Gln Phe Val Val Phe Pro Trp Arg Pro 385 390 395 400tcc aac aaa gtg ctt ggg aag atc tat gat tat ctc atg cac tct ctg 1489 SerAsn Lys Val Leu Gly Lys Ile Tyr Asp Tyr Leu Met His Ser Leu 405 410 415att cat ttc cag gga ttc ttt gtc gcg act atc tac tgc ttc tgt aac 1537 IleHis Phe Gln Gly Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn 420 425 430cat gag gtg caa gtg acc ctg aag cgt cag tgg gcg cag ttc aag atc 1585 HisGlu Val Gln Val Thr Leu Lys Arg Gln Trp Ala Gln Phe Lys Ile 435 440 445cag tgg agc cat cgc tgg ggt agg cgc cgc cgc ccc acc aac cga gtg 1633 GlnTrp Ser His Arg Trp Gly Arg Arg Arg Arg Pro Thr Asn Arg Val 450 455 460gtt agc gct cct cgt gct gta gcc ttt gca gaa cca ggt ggc ctc ccc 1681 ValSer Ala Pro Arg Ala Val Ala Phe Ala Glu Pro Gly Gly Leu Pro 465 470 475480 att tac atc tgc cat cag gaa cca agg aat cct cca gtc agc aac aac 1729Ile Tyr Ile Cys His Gln Glu Pro Arg Asn Pro Pro Val Ser Asn Asn 485 490495 gaa ggc gaa gag ggt act gaa atg atc ccc atg aat gtc atc cag caa 1777Glu Gly Glu Glu Gly Thr Glu Met Ile Pro Met Asn Val Ile Gln Gln 500 505510 gac tca tcc gct tga atgcttgaat gtgaag 1808 Asp Ser Ser Ala 515 32516 PRT Rattus norvegicus 32 Met Arg Phe Leu Leu Leu Asn Arg Phe Thr LeuLeu Leu Leu Leu Leu 1 5 10 15 Val Ser Pro Thr Pro Val Leu Gln Ala ProThr Asn Leu Thr Asp Ser 20 25 30 Gly Leu Asp Gln Glu Pro Phe Leu Tyr LeuVal Gly Arg Lys Lys Leu 35 40 45 Leu Asp Ala Gln Tyr Lys Cys Tyr Asp ArgIle Gln Gln Leu Pro Pro 50 55 60 Tyr Glu Gly Glu Gly Pro Tyr Cys Asn ArgThr Trp Asp Gly Trp Met 65 70 75 80 Cys Trp Asp Asp Thr Pro Ala Gly ValMet Ser Tyr Gln His Cys Pro 85 90 95 Asp Tyr Phe Pro Asp Phe Asp Pro ThrGlu Lys Val Ser Lys Tyr Cys 100 105 110 Asp Glu Asn Gly Glu Trp Phe ArgHis Pro Asp Ser Asn Arg Thr Trp 115 120 125 Ser Asn Tyr Thr Leu Cys AsnAla Phe Thr Pro Asp Lys Leu His Asn 130 135 140 Ala Tyr Val Leu Tyr TyrLeu Ala Leu Val Gly His Ser Met Ser Ile 145 150 155 160 Ala Ala Leu IleAla Ser Met Gly Ile Phe Leu Phe Phe Lys Asn Leu 165 170 175 Ser Cys GlnArg Val Thr Leu His Lys Asn Met Phe Leu Thr Tyr Ile 180 185 190 Leu AsnSer Ile Ile Ile Ile Ile His Leu Val Glu Val Val Pro Asn 195 200 205 GlyAsp Leu Val Arg Arg Asp Pro Met His Ile Phe His His Asn Thr 210 215 220Tyr Met Trp Thr Met Gln Trp Glu Leu Ser Pro Pro Leu Pro Leu Ser 225 230235 240 Ala His Glu Gly Lys Met Asp Pro His Asp Ser Glu Val Ile Ser Cys245 250 255 Lys Ile Leu His Phe Phe His Gln Tyr Met Met Ala Cys Asn TyrPhe 260 265 270 Trp Met Leu Cys Glu Gly Ile Tyr Leu His Thr Leu Ile ValMet Ala 275 280 285 Val Phe Thr Glu Asp Gln Arg Leu Arg Trp Tyr Tyr LeuLeu Gly Trp 290 295 300 Gly Phe Pro Ile Val Pro Thr Ile Ile His Ala IleThr Arg Ala Val 305 310 315 320 Tyr Tyr Asn Asp Asn Cys Trp Leu Ser ThrGlu Thr His Leu Leu Tyr 325 330 335 Ile Ile His Gly Pro Val Met Ala AlaLeu Val Val Asn Phe Phe Phe 340 345 350 Leu Leu Asn Ile Val Arg Val LeuVal Thr Lys Met Arg Gln Thr His 355 360 365 Glu Ala Glu Ala Tyr Met TyrLeu Lys Ala Val Lys Ala Thr Met Val 370 375 380 Leu Val Pro Leu Leu GlyIle Gln Phe Val Val Phe Pro Trp Arg Pro 385 390 395 400 Ser Asn Lys ValLeu Gly Lys Ile Tyr Asp Tyr Leu Met His Ser Leu 405 410 415 Ile His PheGln Gly Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn 420 425 430 His GluVal Gln Val Thr Leu Lys Arg Gln Trp Ala Gln Phe Lys Ile 435 440 445 GlnTrp Ser His Arg Trp Gly Arg Arg Arg Arg Pro Thr Asn Arg Val 450 455 460Val Ser Ala Pro Arg Ala Val Ala Phe Ala Glu Pro Gly Gly Leu Pro 465 470475 480 Ile Tyr Ile Cys His Gln Glu Pro Arg Asn Pro Pro Val Ser Asn Asn485 490 495 Glu Gly Glu Glu Gly Thr Glu Met Ile Pro Met Asn Val Ile GlnGln 500 505 510 Asp Ser Ser Ala 515 33 399 DNA Rattus norvegicus CDS(1)..(330) 33 ccg gac ttt gac cca aca gaa aag gtt tca aaa tac tgc gatgaa aat 48 Pro Asp Phe Asp Pro Thr Glu Lys Val Ser Lys Tyr Cys Asp GluAsn 1 5 10 15 gga gag tgg ttt aga cac cct gac agc aac cga acc tgg tccaac tac 96 Gly Glu Trp Phe Arg His Pro Asp Ser Asn Arg Thr Trp Ser AsnTyr 20 25 30 act ctg tgc aat gcc ttc act cct gac aaa ctg cat aat gca tacgtt 144 Thr Leu Cys Asn Ala Phe Thr Pro Asp Lys Leu His Asn Ala Tyr Val35 40 45 ctt tat tac cta gca ctt gtg ggc cac tcc atg tca att gct gct ctg192 Leu Tyr Tyr Leu Ala Leu Val Gly His Ser Met Ser Ile Ala Ala Leu 5055 60 att gct tcc atg ggg atc ttc ttg ttt ttc aag aac ctt agc tgc cag240 Ile Ala Ser Met Gly Ile Phe Leu Phe Phe Lys Asn Leu Ser Cys Gln 6570 75 80 aga gtg act ctg cac aag aac atg ttc ctc act tat atc ctg aac tct288 Arg Val Thr Leu His Lys Asn Met Phe Leu Thr Tyr Ile Leu Asn Ser 8590 95 atc att atc atc atc cac ctg gtt gag gtt gtg ccc aat gga 330 IleIle Ile Ile Ile His Leu Val Glu Val Val Pro Asn Gly 100 105 110gacctggtgc gacgggatcc tataagttgc aagattctgc actttttcca tcagtacatg 390atggcttgc 399 34 110 PRT Rattus norvegicus 34 Pro Asp Phe Asp Pro ThrGlu Lys Val Ser Lys Tyr Cys Asp Glu Asn 1 5 10 15 Gly Glu Trp Phe ArgHis Pro Asp Ser Asn Arg Thr Trp Ser Asn Tyr 20 25 30 Thr Leu Cys Asn AlaPhe Thr Pro Asp Lys Leu His Asn Ala Tyr Val 35 40 45 Leu Tyr Tyr Leu AlaLeu Val Gly His Ser Met Ser Ile Ala Ala Leu 50 55 60 Ile Ala Ser Met GlyIle Phe Leu Phe Phe Lys Asn Leu Ser Cys Gln 65 70 75 80 Arg Val Thr LeuHis Lys Asn Met Phe Leu Thr Tyr Ile Leu Asn Ser 85 90 95 Ile Ile Ile IleIle His Leu Val Glu Val Val Pro Asn Gly 100 105 110 35 392 DNA Musmusculus CDS (3)..(392) 35 tg gtt gag gtt gtg ccc aat gga gat ctg gtgcgg cgg gat cct ata 47 Val Glu Val Val Pro Asn Gly Asp Leu Val Arg ArgAsp Pro Ile 1 5 10 15 agt tgc aag gtt cta cac ttt tta cat cag tac atgatg tct tgc aac 95 Ser Cys Lys Val Leu His Phe Leu His Gln Tyr Met MetSer Cys Asn 20 25 30 tac ttc tgg atg ctc tgc gag ggg atc tat ctt cat actctg att gtc 143 Tyr Phe Trp Met Leu Cys Glu Gly Ile Tyr Leu His Thr LeuIle Val 35 40 45 atg gct gtg ttt acc gac gag caa cgc cta cgc tgg tac tatctt ctt 191 Met Ala Val Phe Thr Asp Glu Gln Arg Leu Arg Trp Tyr Tyr LeuLeu 50 55 60 ggc tgg ggg ttc ccg ata gtg cca acc att atc cac gcc atc actcgt 239 Gly Trp Gly Phe Pro Ile Val Pro Thr Ile Ile His Ala Ile Thr Arg65 70 75 gcc ctc tac tac aac gac aac tgc tgg ctg agt gca gaa acc cac ttg287 Ala Leu Tyr Tyr Asn Asp Asn Cys Trp Leu Ser Ala Glu Thr His Leu 8085 90 95 ctt tac atc atc cat gga ccc gtc atg gtg gct ctg gtg gtc agc ttc335 Leu Tyr Ile Ile His Gly Pro Val Met Val Ala Leu Val Val Ser Phe 100105 110 ttc ttt ctt ctc aac att gtc cgc gtg ctt gtg acc aag atg agg caa383 Phe Phe Leu Leu Asn Ile Val Arg Val Leu Val Thr Lys Met Arg Gln 115120 125 acc cac gag 392 Thr His Glu 130 36 130 PRT Mus musculus 36 ValGlu Val Val Pro Asn Gly Asp Leu Val Arg Arg Asp Pro Ile Ser 1 5 10 15Cys Lys Val Leu His Phe Leu His Gln Tyr Met Met Ser Cys Asn Tyr 20 25 30Phe Trp Met Leu Cys Glu Gly Ile Tyr Leu His Thr Leu Ile Val Met 35 40 45Ala Val Phe Thr Asp Glu Gln Arg Leu Arg Trp Tyr Tyr Leu Leu Gly 50 55 60Trp Gly Phe Pro Ile Val Pro Thr Ile Ile His Ala Ile Thr Arg Ala 65 70 7580 Leu Tyr Tyr Asn Asp Asn Cys Trp Leu Ser Ala Glu Thr His Leu Leu 85 9095 Tyr Ile Ile His Gly Pro Val Met Val Ala Leu Val Val Ser Phe Phe 100105 110 Phe Leu Leu Asn Ile Val Arg Val Leu Val Thr Lys Met Arg Gln Thr115 120 125 His Glu 130 37 1488 DNA Mus musculus CDS (1)..(1488) 37 atgact cca agg agg tcc aga gtg aaa agg cgg aat ctc cgc aaa ccg 48 Met ThrPro Arg Arg Ser Arg Val Lys Arg Arg Asn Leu Arg Lys Pro 1 5 10 15 aagatg agg ttc ctt ctc gtg aac agg ttc acc ctg ctg ctc ctg ctc 96 Lys MetArg Phe Leu Leu Val Asn Arg Phe Thr Leu Leu Leu Leu Leu 20 25 30 cta gtgagc cca act cca gtt ctt cag gct cct acc aat ctc act gac 144 Leu Val SerPro Thr Pro Val Leu Gln Ala Pro Thr Asn Leu Thr Asp 35 40 45 tcc ggc cttgat cag gag cca ttc ctg tac ttg gtt ggc cgc aag aag 192 Ser Gly Leu AspGln Glu Pro Phe Leu Tyr Leu Val Gly Arg Lys Lys 50 55 60 ctg ctg gat gctcag tac aaa tgc tat gac cgg att cat cag ttg ccc 240 Leu Leu Asp Ala GlnTyr Lys Cys Tyr Asp Arg Ile His Gln Leu Pro 65 70 75 80 tct tat gaa ggagaa ggt ctg tac tgc aac cgc acc tgg gat ggc tgg 288 Ser Tyr Glu Gly GluGly Leu Tyr Cys Asn Arg Thr Trp Asp Gly Trp 85 90 95 atg tgc tgg gac gacact ccc gct gga gcc aca gcc tat cag cac tgc 336 Met Cys Trp Asp Asp ThrPro Ala Gly Ala Thr Ala Tyr Gln His Cys 100 105 110 cct gac tac ttc ccggac ttt gac aca gca gaa aag gtt tca aaa tac 384 Pro Asp Tyr Phe Pro AspPhe Asp Thr Ala Glu Lys Val Ser Lys Tyr 115 120 125 tgt gat gaa aat ggagag tgg ttt aga cac cct gac agc aac cga acc 432 Cys Asp Glu Asn Gly GluTrp Phe Arg His Pro Asp Ser Asn Arg Thr 130 135 140 tgg tcc aac tat actctg tgc aac gct ttc act tct gag aaa ctg caa 480 Trp Ser Asn Tyr Thr LeuCys Asn Ala Phe Thr Ser Glu Lys Leu Gln 145 150 155 160 aat gcg tac gttctt tat tac ctg gct ctt gtg ggt cac tcc ttg tcg 528 Asn Ala Tyr Val LeuTyr Tyr Leu Ala Leu Val Gly His Ser Leu Ser 165 170 175 att gct gct ttggtt gct tcc atg ctg atc ttc tgg att ttc aag aac 576 Ile Ala Ala Leu ValAla Ser Met Leu Ile Phe Trp Ile Phe Lys Asn 180 185 190 ctt agc tgc cagagg gtg acc ttg cac aag cac atg ttc ctt act tat 624 Leu Ser Cys Gln ArgVal Thr Leu His Lys His Met Phe Leu Thr Tyr 195 200 205 att ctg aat tctatc att atc atc atc cac ctg gtt gag gtt gtg ccc 672 Ile Leu Asn Ser IleIle Ile Ile Ile His Leu Val Glu Val Val Pro 210 215 220 aat gga gat ctggtg cgg cgg gat cct ata agt tgc aag gtt cta cac 720 Asn Gly Asp Leu ValArg Arg Asp Pro Ile Ser Cys Lys Val Leu His 225 230 235 240 ttt tta catcag tac atg atg tct tgc aac tac ttc tgg atg ctc tgc 768 Phe Leu His GlnTyr Met Met Ser Cys Asn Tyr Phe Trp Met Leu Cys 245 250 255 gag ggg atctat ctt cat act ctg att gtc atg gct gtg ttt acc gac 816 Glu Gly Ile TyrLeu His Thr Leu Ile Val Met Ala Val Phe Thr Asp 260 265 270 gag caa cgccta cgc tgg tac tat ctt ctt ggc tgg ggg ttc ccg ata 864 Glu Gln Arg LeuArg Trp Tyr Tyr Leu Leu Gly Trp Gly Phe Pro Ile 275 280 285 gtg cca accatt atc cac gcc atc act cgt gcc ctc tac tac aac gac 912 Val Pro Thr IleIle His Ala Ile Thr Arg Ala Leu Tyr Tyr Asn Asp 290 295 300 aac tgc tggctg agt gca gaa acc cac ttg ctt tac atc atc cat gga 960 Asn Cys Trp LeuSer Ala Glu Thr His Leu Leu Tyr Ile Ile His Gly 305 310 315 320 ccc gtcatg gtg gct ctg gtg gtc aac ttc ttc ttt ctt ctc aac att 1008 Pro Val MetVal Ala Leu Val Val Asn Phe Phe Phe Leu Leu Asn Ile 325 330 335 gtc cgcgtg ctt gtg acc aag atg agg caa acc cac gag gcc gag tcc 1056 Val Arg ValLeu Val Thr Lys Met Arg Gln Thr His Glu Ala Glu Ser 340 345 350 tac atgtac ctg aag gct gtg aag gcc acc atg gtc ctt gtg ccc ctg 1104 Tyr Met TyrLeu Lys Ala Val Lys Ala Thr Met Val Leu Val Pro Leu 355 360 365 ctg gggatc cag ttt gtt gtg ttt ccc tgg agg ccc tcc aac aag gtg 1152 Leu Gly IleGln Phe Val Val Phe Pro Trp Arg Pro Ser Asn Lys Val 370 375 380 ctt gggaag atc tat gat tat ctc atg cac tct ctg att cat ttc cag 1200 Leu Gly LysIle Tyr Asp Tyr Leu Met His Ser Leu Ile His Phe Gln 385 390 395 400 ggattc ttt gtg gcg act atc tac tgc ttc tgc aac cat gag gtg caa 1248 Gly PhePhe Val Ala Thr Ile Tyr Cys Phe Cys Asn His Glu Val Gln 405 410 415 gtcacc ctg aag cgc cag tgg acg cag ttc aag atc cag tgg agc caa 1296 Val ThrLeu Lys Arg Gln Trp Thr Gln Phe Lys Ile Gln Trp Ser Gln 420 425 430 cgctgg gga agg cgc cgc ccc acc aac cgc gta gtt agt gct cct cgg 1344 Arg TrpGly Arg Arg Arg Pro Thr Asn Arg Val Val Ser Ala Pro Arg 435 440 445 gctgta gcc ttc gct gag cca gat ggc ctc ccc att tac atc tgc cat 1392 Ala ValAla Phe Ala Glu Pro Asp Gly Leu Pro Ile Tyr Ile Cys His 450 455 460 caggaa cca cgg aat cct cca atc agc aac aac gaa ggc gag gag agt 1440 Gln GluPro Arg Asn Pro Pro Ile Ser Asn Asn Glu Gly Glu Glu Ser 465 470 475 480act gaa atg atc ccc atg aac gtc atc cag caa gac gca tcc gct tga 1488 ThrGlu Met Ile Pro Met Asn Val Ile Gln Gln Asp Ala Ser Ala 485 490 495 38495 PRT Mus musculus 38 Met Thr Pro Arg Arg Ser Arg Val Lys Arg Arg AsnLeu Arg Lys Pro 1 5 10 15 Lys Met Arg Phe Leu Leu Val Asn Arg Phe ThrLeu Leu Leu Leu Leu 20 25 30 Leu Val Ser Pro Thr Pro Val Leu Gln Ala ProThr Asn Leu Thr Asp 35 40 45 Ser Gly Leu Asp Gln Glu Pro Phe Leu Tyr LeuVal Gly Arg Lys Lys 50 55 60 Leu Leu Asp Ala Gln Tyr Lys Cys Tyr Asp ArgIle His Gln Leu Pro 65 70 75 80 Ser Tyr Glu Gly Glu Gly Leu Tyr Cys AsnArg Thr Trp Asp Gly Trp 85 90 95 Met Cys Trp Asp Asp Thr Pro Ala Gly AlaThr Ala Tyr Gln His Cys 100 105 110 Pro Asp Tyr Phe Pro Asp Phe Asp ThrAla Glu Lys Val Ser Lys Tyr 115 120 125 Cys Asp Glu Asn Gly Glu Trp PheArg His Pro Asp Ser Asn Arg Thr 130 135 140 Trp Ser Asn Tyr Thr Leu CysAsn Ala Phe Thr Ser Glu Lys Leu Gln 145 150 155 160 Asn Ala Tyr Val LeuTyr Tyr Leu Ala Leu Val Gly His Ser Leu Ser 165 170 175 Ile Ala Ala LeuVal Ala Ser Met Leu Ile Phe Trp Ile Phe Lys Asn 180 185 190 Leu Ser CysGln Arg Val Thr Leu His Lys His Met Phe Leu Thr Tyr 195 200 205 Ile LeuAsn Ser Ile Ile Ile Ile Ile His Leu Val Glu Val Val Pro 210 215 220 AsnGly Asp Leu Val Arg Arg Asp Pro Ile Ser Cys Lys Val Leu His 225 230 235240 Phe Leu His Gln Tyr Met Met Ser Cys Asn Tyr Phe Trp Met Leu Cys 245250 255 Glu Gly Ile Tyr Leu His Thr Leu Ile Val Met Ala Val Phe Thr Asp260 265 270 Glu Gln Arg Leu Arg Trp Tyr Tyr Leu Leu Gly Trp Gly Phe ProIle 275 280 285 Val Pro Thr Ile Ile His Ala Ile Thr Arg Ala Leu Tyr TyrAsn Asp 290 295 300 Asn Cys Trp Leu Ser Ala Glu Thr His Leu Leu Tyr IleIle His Gly 305 310 315 320 Pro Val Met Val Ala Leu Val Val Asn Phe PhePhe Leu Leu Asn Ile 325 330 335 Val Arg Val Leu Val Thr Lys Met Arg GlnThr His Glu Ala Glu Ser 340 345 350 Tyr Met Tyr Leu Lys Ala Val Lys AlaThr Met Val Leu Val Pro Leu 355 360 365 Leu Gly Ile Gln Phe Val Val PhePro Trp Arg Pro Ser Asn Lys Val 370 375 380 Leu Gly Lys Ile Tyr Asp TyrLeu Met His Ser Leu Ile His Phe Gln 385 390 395 400 Gly Phe Phe Val AlaThr Ile Tyr Cys Phe Cys Asn His Glu Val Gln 405 410 415 Val Thr Leu LysArg Gln Trp Thr Gln Phe Lys Ile Gln Trp Ser Gln 420 425 430 Arg Trp GlyArg Arg Arg Pro Thr Asn Arg Val Val Ser Ala Pro Arg 435 440 445 Ala ValAla Phe Ala Glu Pro Asp Gly Leu Pro Ile Tyr Ile Cys His 450 455 460 GlnGlu Pro Arg Asn Pro Pro Ile Ser Asn Asn Glu Gly Glu Glu Ser 465 470 475480 Thr Glu Met Ile Pro Met Asn Val Ile Gln Gln Asp Ala Ser Ala 485 490495 39 1437 DNA Mus musculus CDS (1)..(1437) 39 atg agg ttc ctt ctc gtgaac agg ttc acc ctg ctg ctc ctg ctc cta 48 Met Arg Phe Leu Leu Val AsnArg Phe Thr Leu Leu Leu Leu Leu Leu 1 5 10 15 gtg agc cca act cca gttctt cag gct cct acc aat ctc act gac tcc 96 Val Ser Pro Thr Pro Val LeuGln Ala Pro Thr Asn Leu Thr Asp Ser 20 25 30 ggc ctt gat cag gag cca ttcctg tac ttg gtt ggc cgc aag aag ctg 144 Gly Leu Asp Gln Glu Pro Phe LeuTyr Leu Val Gly Arg Lys Lys Leu 35 40 45 ctg gat gct cag tac aaa tgc tatgac cgg att cat cag ttg ccc tct 192 Leu Asp Ala Gln Tyr Lys Cys Tyr AspArg Ile His Gln Leu Pro Ser 50 55 60 tat gaa gga gaa ggt ctg tac tgc aaccgc acc tgg gat ggc tgg atg 240 Tyr Glu Gly Glu Gly Leu Tyr Cys Asn ArgThr Trp Asp Gly Trp Met 65 70 75 80 tgc tgg gac gac act ccc gct gga gccaca gcc tat cag cac tgc cct 288 Cys Trp Asp Asp Thr Pro Ala Gly Ala ThrAla Tyr Gln His Cys Pro 85 90 95 gac tac ttc ccg gac ttt gac aca gca gaaaag gtt tca aaa tac tgt 336 Asp Tyr Phe Pro Asp Phe Asp Thr Ala Glu LysVal Ser Lys Tyr Cys 100 105 110 gat gaa aat gga gag tgg ttt aga cac cctgac agc aac cga acc tgg 384 Asp Glu Asn Gly Glu Trp Phe Arg His Pro AspSer Asn Arg Thr Trp 115 120 125 tcc aac tat act ctg tgc aac gct ttc acttct gag aaa ctg caa aat 432 Ser Asn Tyr Thr Leu Cys Asn Ala Phe Thr SerGlu Lys Leu Gln Asn 130 135 140 gcg tac gtt ctt tat tac ctg gct ctt gtgggt cac tcc ttg tcg att 480 Ala Tyr Val Leu Tyr Tyr Leu Ala Leu Val GlyHis Ser Leu Ser Ile 145 150 155 160 gct gct ttg gtt gct tcc atg ctg atcttc tgg att ttc aag aac ctt 528 Ala Ala Leu Val Ala Ser Met Leu Ile PheTrp Ile Phe Lys Asn Leu 165 170 175 agc tgc cag agg gtg acc ttg cac aagcac atg ttc ctt act tat att 576 Ser Cys Gln Arg Val Thr Leu His Lys HisMet Phe Leu Thr Tyr Ile 180 185 190 ctg aat tct atc att atc atc atc cacctg gtt gag gtt gtg ccc aat 624 Leu Asn Ser Ile Ile Ile Ile Ile His LeuVal Glu Val Val Pro Asn 195 200 205 gga gat ctg gtg cgg cgg gat cct ataagt tgc aag gtt cta cac ttt 672 Gly Asp Leu Val Arg Arg Asp Pro Ile SerCys Lys Val Leu His Phe 210 215 220 tta cat cag tac atg atg tct tgc aactac ttc tgg atg ctc tgc gag 720 Leu His Gln Tyr Met Met Ser Cys Asn TyrPhe Trp Met Leu Cys Glu 225 230 235 240 ggg atc tat ctt cat act ctg attgtc atg gct gtg ttt acc gac gag 768 Gly Ile Tyr Leu His Thr Leu Ile ValMet Ala Val Phe Thr Asp Glu 245 250 255 caa cgc cta cgc tgg tac tat cttctt ggc tgg ggg ttc ccg ata gtg 816 Gln Arg Leu Arg Trp Tyr Tyr Leu LeuGly Trp Gly Phe Pro Ile Val 260 265 270 cca acc att atc cac gcc atc actcgt gcc ctc tac tac aac gac aac 864 Pro Thr Ile Ile His Ala Ile Thr ArgAla Leu Tyr Tyr Asn Asp Asn 275 280 285 tgc tgg ctg agt gca gaa acc cacttg ctt tac atc atc cat gga ccc 912 Cys Trp Leu Ser Ala Glu Thr His LeuLeu Tyr Ile Ile His Gly Pro 290 295 300 gtc atg gtg gct ctg gtg gtc aacttc ttc ttt ctt ctc aac att gtc 960 Val Met Val Ala Leu Val Val Asn PhePhe Phe Leu Leu Asn Ile Val 305 310 315 320 cgc gtg ctt gtg acc aag atgagg caa acc cac gag gcc gag tcc tac 1008 Arg Val Leu Val Thr Lys Met ArgGln Thr His Glu Ala Glu Ser Tyr 325 330 335 atg tac ctg aag gct gtg aaggcc acc atg gtc ctt gtg ccc ctg ctg 1056 Met Tyr Leu Lys Ala Val Lys AlaThr Met Val Leu Val Pro Leu Leu 340 345 350 ggg atc cag ttt gtt gtg tttccc tgg agg ccc tcc aac aag gtg ctt 1104 Gly Ile Gln Phe Val Val Phe ProTrp Arg Pro Ser Asn Lys Val Leu 355 360 365 ggg aag atc tat gat tat ctcatg cac tct ctg att cat ttc cag gga 1152 Gly Lys Ile Tyr Asp Tyr Leu MetHis Ser Leu Ile His Phe Gln Gly 370 375 380 ttc ttt gtg gcg act atc tactgc ttc tgc aac cat gag gtg caa gtc 1200 Phe Phe Val Ala Thr Ile Tyr CysPhe Cys Asn His Glu Val Gln Val 385 390 395 400 acc ctg aag cgc cag tggacg cag ttc aag atc cag tgg agc caa cgc 1248 Thr Leu Lys Arg Gln Trp ThrGln Phe Lys Ile Gln Trp Ser Gln Arg 405 410 415 tgg gga agg cgc cgc cccacc aac cgc gta gtt agt gct cct cgg gct 1296 Trp Gly Arg Arg Arg Pro ThrAsn Arg Val Val Ser Ala Pro Arg Ala 420 425 430 gta gcc ttc gct gag ccagat ggc ctc ccc att tac atc tgc cat cag 1344 Val Ala Phe Ala Glu Pro AspGly Leu Pro Ile Tyr Ile Cys His Gln 435 440 445 gaa cca cgg aat cct ccaatc agc aac aac gaa ggc gag gag agt act 1392 Glu Pro Arg Asn Pro Pro IleSer Asn Asn Glu Gly Glu Glu Ser Thr 450 455 460 gaa atg atc ccc atg aacgtc atc cag caa gac gca tcc gct tga 1437 Glu Met Ile Pro Met Asn Val IleGln Gln Asp Ala Ser Ala 465 470 475 40 478 PRT Mus musculus 40 Met ArgPhe Leu Leu Val Asn Arg Phe Thr Leu Leu Leu Leu Leu Leu 1 5 10 15 ValSer Pro Thr Pro Val Leu Gln Ala Pro Thr Asn Leu Thr Asp Ser 20 25 30 GlyLeu Asp Gln Glu Pro Phe Leu Tyr Leu Val Gly Arg Lys Lys Leu 35 40 45 LeuAsp Ala Gln Tyr Lys Cys Tyr Asp Arg Ile His Gln Leu Pro Ser 50 55 60 TyrGlu Gly Glu Gly Leu Tyr Cys Asn Arg Thr Trp Asp Gly Trp Met 65 70 75 80Cys Trp Asp Asp Thr Pro Ala Gly Ala Thr Ala Tyr Gln His Cys Pro 85 90 95Asp Tyr Phe Pro Asp Phe Asp Thr Ala Glu Lys Val Ser Lys Tyr Cys 100 105110 Asp Glu Asn Gly Glu Trp Phe Arg His Pro Asp Ser Asn Arg Thr Trp 115120 125 Ser Asn Tyr Thr Leu Cys Asn Ala Phe Thr Ser Glu Lys Leu Gln Asn130 135 140 Ala Tyr Val Leu Tyr Tyr Leu Ala Leu Val Gly His Ser Leu SerIle 145 150 155 160 Ala Ala Leu Val Ala Ser Met Leu Ile Phe Trp Ile PheLys Asn Leu 165 170 175 Ser Cys Gln Arg Val Thr Leu His Lys His Met PheLeu Thr Tyr Ile 180 185 190 Leu Asn Ser Ile Ile Ile Ile Ile His Leu ValGlu Val Val Pro Asn 195 200 205 Gly Asp Leu Val Arg Arg Asp Pro Ile SerCys Lys Val Leu His Phe 210 215 220 Leu His Gln Tyr Met Met Ser Cys AsnTyr Phe Trp Met Leu Cys Glu 225 230 235 240 Gly Ile Tyr Leu His Thr LeuIle Val Met Ala Val Phe Thr Asp Glu 245 250 255 Gln Arg Leu Arg Trp TyrTyr Leu Leu Gly Trp Gly Phe Pro Ile Val 260 265 270 Pro Thr Ile Ile HisAla Ile Thr Arg Ala Leu Tyr Tyr Asn Asp Asn 275 280 285 Cys Trp Leu SerAla Glu Thr His Leu Leu Tyr Ile Ile His Gly Pro 290 295 300 Val Met ValAla Leu Val Val Asn Phe Phe Phe Leu Leu Asn Ile Val 305 310 315 320 ArgVal Leu Val Thr Lys Met Arg Gln Thr His Glu Ala Glu Ser Tyr 325 330 335Met Tyr Leu Lys Ala Val Lys Ala Thr Met Val Leu Val Pro Leu Leu 340 345350 Gly Ile Gln Phe Val Val Phe Pro Trp Arg Pro Ser Asn Lys Val Leu 355360 365 Gly Lys Ile Tyr Asp Tyr Leu Met His Ser Leu Ile His Phe Gln Gly370 375 380 Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn His Glu Val GlnVal 385 390 395 400 Thr Leu Lys Arg Gln Trp Thr Gln Phe Lys Ile Gln TrpSer Gln Arg 405 410 415 Trp Gly Arg Arg Arg Pro Thr Asn Arg Val Val SerAla Pro Arg Ala 420 425 430 Val Ala Phe Ala Glu Pro Asp Gly Leu Pro IleTyr Ile Cys His Gln 435 440 445 Glu Pro Arg Asn Pro Pro Ile Ser Asn AsnGlu Gly Glu Glu Ser Thr 450 455 460 Glu Met Ile Pro Met Asn Val Ile GlnGln Asp Ala Ser Ala 465 470 475 41 3731 DNA Mus musculus CDS(508)..(2055) 41 aattcggcac gaggctgcac ccagctccgg ataggaggtg gaggatagcccgtccttgga 60 agcaacttgc tttcctccca gggtgcgcct gccagcccag actgcgcccgcctggaatca 120 gattgtccgg gctcctgctg gctttcagtg gagaagggga attgtcctcaacaccaagtc 180 aggagagcca gccgccccaa agactctggg cgactgcacc tggctggcttgcagacaact 240 cttggttgga gaggtgctta cttctgcgcc tcacgctgcc gttggccatccctgcctgca 300 gatgcccagt gaaggtctgc tttcctgaga acacctgagc tgtgcccagacatccagcaa 360 gagaattcct gcatccacct aaggtaagtg ccattagagc gccttccagaggagaagaaa 420 ccgagggagc agggctacta cacagaggat ttgaaaatga ctccaaggaggtccagagtg 480 aaaaggcgga atctccgcaa accgaag atg agg ttc ctt ctc gtg aacagg ttc 534 Met Arg Phe Leu Leu Val Asn Arg Phe 1 5 acc ctg ctg ctc ctgctc cta gtg agc cca act cca gtt ctt cag gct 582 Thr Leu Leu Leu Leu LeuLeu Val Ser Pro Thr Pro Val Leu Gln Ala 10 15 20 25 cct acc aat ctc actgac tcc ggc ctt gat cag gag cca ttc ctg tac 630 Pro Thr Asn Leu Thr AspSer Gly Leu Asp Gln Glu Pro Phe Leu Tyr 30 35 40 ttg gtt ggc cgc aag aagctg ctg gat gct cag tac aaa tgc tat gac 678 Leu Val Gly Arg Lys Lys LeuLeu Asp Ala Gln Tyr Lys Cys Tyr Asp 45 50 55 cgg att cat cag ttg ccc tcttat gaa gga gaa ggt ctg tac tgc aac 726 Arg Ile His Gln Leu Pro Ser TyrGlu Gly Glu Gly Leu Tyr Cys Asn 60 65 70 cgc acc tgg gat ggc tgg atg tgctgg gac gac act ccc gct gga gcc 774 Arg Thr Trp Asp Gly Trp Met Cys TrpAsp Asp Thr Pro Ala Gly Ala 75 80 85 aca gcc tat cag cac tgc cct gac tacttc ccg gac ttt gac aca gca 822 Thr Ala Tyr Gln His Cys Pro Asp Tyr PhePro Asp Phe Asp Thr Ala 90 95 100 105 gaa aag gtt tca aaa tac tgt gatgaa aat gga gag tgg ttt aga cac 870 Glu Lys Val Ser Lys Tyr Cys Asp GluAsn Gly Glu Trp Phe Arg His 110 115 120 cct gac agc aac cga acc tgg tccaac tat act ctg tgc aac gct ttc 918 Pro Asp Ser Asn Arg Thr Trp Ser AsnTyr Thr Leu Cys Asn Ala Phe 125 130 135 act tct gag aaa ctg caa aat gcgtac gtt ctt tat tac ctg gct ctt 966 Thr Ser Glu Lys Leu Gln Asn Ala TyrVal Leu Tyr Tyr Leu Ala Leu 140 145 150 gtg ggt cac tcc ttg tcg att gctgct ttg gtt gct tcc atg ctg atc 1014 Val Gly His Ser Leu Ser Ile Ala AlaLeu Val Ala Ser Met Leu Ile 155 160 165 ttc tgg att ttc aag aac ctt agctgc cag agg gtg acc ttg cac aag 1062 Phe Trp Ile Phe Lys Asn Leu Ser CysGln Arg Val Thr Leu His Lys 170 175 180 185 cac atg ttc ctt act tat attctg aat tct atc att atc atc atc cac 1110 His Met Phe Leu Thr Tyr Ile LeuAsn Ser Ile Ile Ile Ile Ile His 190 195 200 ctg gtt gag gtt gtg ccc aatgga gat ctg gtg cgg cgg gat cct atg 1158 Leu Val Glu Val Val Pro Asn GlyAsp Leu Val Arg Arg Asp Pro Met 205 210 215 cat att ttt cat cat aac acacat atg tgg aca atg cag tgg gaa ctg 1206 His Ile Phe His His Asn Thr HisMet Trp Thr Met Gln Trp Glu Leu 220 225 230 tca cca ccc tta ccc ctg tgtgca cac gag gga aag atg gac cct cat 1254 Ser Pro Pro Leu Pro Leu Cys AlaHis Glu Gly Lys Met Asp Pro His 235 240 245 gcc agt gaa gtg ata agt tgcaag gtt cta cac ttt tta cat cag tac 1302 Ala Ser Glu Val Ile Ser Cys LysVal Leu His Phe Leu His Gln Tyr 250 255 260 265 atg atg tct tgc aac tacttc tgg atg ctc tgc gag ggg atc tat ctt 1350 Met Met Ser Cys Asn Tyr PheTrp Met Leu Cys Glu Gly Ile Tyr Leu 270 275 280 cat act ctg att gtc atggct gtg ttt acc gac gag caa cgc cta cgc 1398 His Thr Leu Ile Val Met AlaVal Phe Thr Asp Glu Gln Arg Leu Arg 285 290 295 tgg tac tat ctt ctt ggctgg ggg ttc ccg ata gtg cca acc att atc 1446 Trp Tyr Tyr Leu Leu Gly TrpGly Phe Pro Ile Val Pro Thr Ile Ile 300 305 310 cac gcc atc act cgt gccctc tac tac aac gac aac tgc tgg ctg agt 1494 His Ala Ile Thr Arg Ala LeuTyr Tyr Asn Asp Asn Cys Trp Leu Ser 315 320 325 gca gaa acc cac ttg ctttac atc atc cat gga ccc gtc atg gtg gct 1542 Ala Glu Thr His Leu Leu TyrIle Ile His Gly Pro Val Met Val Ala 330 335 340 345 ctg gtg gtc aac ttcttc ttt ctt ctc aac att gtc cgc gtg ctt gtg 1590 Leu Val Val Asn Phe PhePhe Leu Leu Asn Ile Val Arg Val Leu Val 350 355 360 acc aag atg agg caaacc cac gag gcc gag tcc tac atg tac ctg aag 1638 Thr Lys Met Arg Gln ThrHis Glu Ala Glu Ser Tyr Met Tyr Leu Lys 365 370 375 gct gtg aag gcc accatg gtc ctt gtg ccc ctg ctg ggg atc cag ttt 1686 Ala Val Lys Ala Thr MetVal Leu Val Pro Leu Leu Gly Ile Gln Phe 380 385 390 gtt gtg ttt ccc tggagg ccc tcc aac aag gtg ctt ggg aag atc tat 1734 Val Val Phe Pro Trp ArgPro Ser Asn Lys Val Leu Gly Lys Ile Tyr 395 400 405 gat tat ctc atg cactct ctg att cat ttc cag gga ttc ttt gtg gcg 1782 Asp Tyr Leu Met His SerLeu Ile His Phe Gln Gly Phe Phe Val Ala 410 415 420 425 act atc tac tgcttc tgc aac cat gag gtg caa gtc acc ctg aag cgc 1830 Thr Ile Tyr Cys PheCys Asn His Glu Val Gln Val Thr Leu Lys Arg 430 435 440 cag tgg acg cagttc aag atc cag tgg agc caa cgc tgg gga agg cgc 1878 Gln Trp Thr Gln PheLys Ile Gln Trp Ser Gln Arg Trp Gly Arg Arg 445 450 455 cgc ccc acc aaccgc gta gtt agt gct cct cgg gct gta gcc ttc gct 1926 Arg Pro Thr Asn ArgVal Val Ser Ala Pro Arg Ala Val Ala Phe Ala 460 465 470 gag cca gat ggcctc ccc att tac atc tgc cat cag gaa cca cgg aat 1974 Glu Pro Asp Gly LeuPro Ile Tyr Ile Cys His Gln Glu Pro Arg Asn 475 480 485 cct cca atc agcaac aac gaa ggc gag gag agt act gaa atg atc ccc 2022 Pro Pro Ile Ser AsnAsn Glu Gly Glu Glu Ser Thr Glu Met Ile Pro 490 495 500 505 atg aac gtcatc cag caa gac gca tcc gct tga atgtgaagcc accccaagca 2075 Met Asn ValIle Gln Gln Asp Ala Ser Ala 510 515 ttgtgatcca ctgagccttc atttcctggggaaagacaga ccatgtgttt caagtgattc 2135 ccatcctccc aggagctgac catatcatttgtgaagaagt gttaagtgaa tttgtccata 2195 gtgaatttga agaaagtgat tcttggtactattgctttgg gagtcagtct aggaatagag 2255 tctcccattg caacttgtga actccatcattcatcctgga ctgagatgac tgtgttcgta 2315 ggaaagcagg caaggtgttc aaaagatgtcacactattga cctagttcag atacagggtg 2375 ctcccttgtg aaattttgag ccatttgtaccgttgagaaa ttaaaatcac tctcaatgtt 2435 tttaaatttg acactggatt ttgaattagactatttctgt atttgactac agatctggtt 2495 tttaatgttt ttatttcagt cagttcctatattacacatg ttaccatcca tacaatgtca 2555 actacacata tagcatgacc tctgaaagatggtgtgtctt ttataacatg atccagttca 2615 ccaggcagac ccaaagtgct gtaatgaattgatctgaacc ttgtatgtgc tttggtcact 2675 gacatttata agttgggagg tcaccaagaacctatcacca aatttatcac aaaactgccc 2735 tccaaaatgt aacaatcttt aaagagagttttcacttttc ctaaactaca aggaatttag 2795 tcaagagacc agagtcactc caaggattataaaagcaaga ttaacctctt gcccttgggt 2855 gctatctagc agtaagagaa gatttgtttacgaactggta attaaagact cctatacaag 2915 tccattaact gccttccacc cagcttcaaagctaaacaag atccctgtgt tttcaagaag 2975 actctgtgtg gctaattaca aatcagtttcttgttgacct cttgcttgct gctattagca 3035 aaacaagagg gggaaaaaac ccacaatgtagggacttcaa atttaacctc atattaattc 3095 atcttaaatt aaaaacagag cttctcatcaaaacccagta ctatatctcc atacccatct 3155 ctttactccc cagtaggaga tcatctaagatccatgaata aaccaatacc atcacagatt 3215 tctgaatctg caacagtaac cagtcatcattacttaattt gtatgctaaa tgaggagctt 3275 ttttgagacc ctcaaaatct cctgctcacctttgtaatct tttgtcactg cctttcagag 3335 gtgatttagt tgtgtaaaga caaaagtaacttgatttgtt ctggttacat gcttggtgta 3395 cccagagaaa ctgtatttca atagcaactgtggaccttgg atactgagag ttgcctttac 3455 caaaatggaa ggacggattg aaggaaggatgttttttcaa tcacagtgtt acctggtgat 3515 gtccctatgt tttgtttaca cacatcgaaatcagtgtatt tcaggcagct ctagtacaaa 3575 tgtgataata tattgaagtg tttgagatgttattgtgctt atgtagtagg agctgatgaa 3635 atcaaactga cttaccataa cattgcatgtcatacctaaa ttgtgggaaa cgcttctgct 3695 gtgtacatgt ataaatacag agcatattaaaaaggc 3731 42 515 PRT Mus musculus 42 Met Arg Phe Leu Leu Val Asn ArgPhe Thr Leu Leu Leu Leu Leu Leu 1 5 10 15 Val Ser Pro Thr Pro Val LeuGln Ala Pro Thr Asn Leu Thr Asp Ser 20 25 30 Gly Leu Asp Gln Glu Pro PheLeu Tyr Leu Val Gly Arg Lys Lys Leu 35 40 45 Leu Asp Ala Gln Tyr Lys CysTyr Asp Arg Ile His Gln Leu Pro Ser 50 55 60 Tyr Glu Gly Glu Gly Leu TyrCys Asn Arg Thr Trp Asp Gly Trp Met 65 70 75 80 Cys Trp Asp Asp Thr ProAla Gly Ala Thr Ala Tyr Gln His Cys Pro 85 90 95 Asp Tyr Phe Pro Asp PheAsp Thr Ala Glu Lys Val Ser Lys Tyr Cys 100 105 110 Asp Glu Asn Gly GluTrp Phe Arg His Pro Asp Ser Asn Arg Thr Trp 115 120 125 Ser Asn Tyr ThrLeu Cys Asn Ala Phe Thr Ser Glu Lys Leu Gln Asn 130 135 140 Ala Tyr ValLeu Tyr Tyr Leu Ala Leu Val Gly His Ser Leu Ser Ile 145 150 155 160 AlaAla Leu Val Ala Ser Met Leu Ile Phe Trp Ile Phe Lys Asn Leu 165 170 175Ser Cys Gln Arg Val Thr Leu His Lys His Met Phe Leu Thr Tyr Ile 180 185190 Leu Asn Ser Ile Ile Ile Ile Ile His Leu Val Glu Val Val Pro Asn 195200 205 Gly Asp Leu Val Arg Arg Asp Pro Met His Ile Phe His His Asn Thr210 215 220 His Met Trp Thr Met Gln Trp Glu Leu Ser Pro Pro Leu Pro LeuCys 225 230 235 240 Ala His Glu Gly Lys Met Asp Pro His Ala Ser Glu ValIle Ser Cys 245 250 255 Lys Val Leu His Phe Leu His Gln Tyr Met Met SerCys Asn Tyr Phe 260 265 270 Trp Met Leu Cys Glu Gly Ile Tyr Leu His ThrLeu Ile Val Met Ala 275 280 285 Val Phe Thr Asp Glu Gln Arg Leu Arg TrpTyr Tyr Leu Leu Gly Trp 290 295 300 Gly Phe Pro Ile Val Pro Thr Ile IleHis Ala Ile Thr Arg Ala Leu 305 310 315 320 Tyr Tyr Asn Asp Asn Cys TrpLeu Ser Ala Glu Thr His Leu Leu Tyr 325 330 335 Ile Ile His Gly Pro ValMet Val Ala Leu Val Val Asn Phe Phe Phe 340 345 350 Leu Leu Asn Ile ValArg Val Leu Val Thr Lys Met Arg Gln Thr His 355 360 365 Glu Ala Glu SerTyr Met Tyr Leu Lys Ala Val Lys Ala Thr Met Val 370 375 380 Leu Val ProLeu Leu Gly Ile Gln Phe Val Val Phe Pro Trp Arg Pro 385 390 395 400 SerAsn Lys Val Leu Gly Lys Ile Tyr Asp Tyr Leu Met His Ser Leu 405 410 415Ile His Phe Gln Gly Phe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn 420 425430 His Glu Val Gln Val Thr Leu Lys Arg Gln Trp Thr Gln Phe Lys Ile 435440 445 Gln Trp Ser Gln Arg Trp Gly Arg Arg Arg Pro Thr Asn Arg Val Val450 455 460 Ser Ala Pro Arg Ala Val Ala Phe Ala Glu Pro Asp Gly Leu ProIle 465 470 475 480 Tyr Ile Cys His Gln Glu Pro Arg Asn Pro Pro Ile SerAsn Asn Glu 485 490 495 Gly Glu Glu Ser Thr Glu Met Ile Pro Met Asn ValIle Gln Gln Asp 500 505 510 Ala Ser Ala 515 43 1548 DNA Mus musculus CDS(1)..(1548) 43 atg agg ttc ctt ctc gtg aac agg ttc acc ctg ctg ctc ctgctc cta 48 Met Arg Phe Leu Leu Val Asn Arg Phe Thr Leu Leu Leu Leu LeuLeu 1 5 10 15 gtg agc cca act cca gtt ctt cag gct cct acc aat ctc actgac tcc 96 Val Ser Pro Thr Pro Val Leu Gln Ala Pro Thr Asn Leu Thr AspSer 20 25 30 ggc ctt gat cag gag cca ttc ctg tac ttg gtt ggc cgc aag aagctg 144 Gly Leu Asp Gln Glu Pro Phe Leu Tyr Leu Val Gly Arg Lys Lys Leu35 40 45 ctg gat gct cag tac aaa tgc tat gac cgg att cat cag ttg ccc tct192 Leu Asp Ala Gln Tyr Lys Cys Tyr Asp Arg Ile His Gln Leu Pro Ser 5055 60 tat gaa gga gaa ggt ctg tac tgc aac cgc acc tgg gat ggc tgg atg240 Tyr Glu Gly Glu Gly Leu Tyr Cys Asn Arg Thr Trp Asp Gly Trp Met 6570 75 80 tgc tgg gac gac act ccc gct gga gcc aca gcc tat cag cac tgc cct288 Cys Trp Asp Asp Thr Pro Ala Gly Ala Thr Ala Tyr Gln His Cys Pro 8590 95 gac tac ttc ccg gac ttt gac aca gca gaa aag gtt tca aaa tac tgt336 Asp Tyr Phe Pro Asp Phe Asp Thr Ala Glu Lys Val Ser Lys Tyr Cys 100105 110 gat gaa aat gga gag tgg ttt aga cac cct gac agc aac cga acc tgg384 Asp Glu Asn Gly Glu Trp Phe Arg His Pro Asp Ser Asn Arg Thr Trp 115120 125 tcc aac tat act ctg tgc aac gct ttc act tct gag aaa ctg caa aat432 Ser Asn Tyr Thr Leu Cys Asn Ala Phe Thr Ser Glu Lys Leu Gln Asn 130135 140 gcg tac gtt ctt tat tac ctg gct ctt gtg ggt cac tcc ttg tcg att480 Ala Tyr Val Leu Tyr Tyr Leu Ala Leu Val Gly His Ser Leu Ser Ile 145150 155 160 gct gct ttg gtt gct tcc atg ctg atc ttc tgg att ttc aag aacctt 528 Ala Ala Leu Val Ala Ser Met Leu Ile Phe Trp Ile Phe Lys Asn Leu165 170 175 agc tgc cag agg gtg acc ttg cac aag cac atg ttc ctt act tatatt 576 Ser Cys Gln Arg Val Thr Leu His Lys His Met Phe Leu Thr Tyr Ile180 185 190 ctg aat tct atc att atc atc atc cac ctg gtt gag gtt gtg cccaat 624 Leu Asn Ser Ile Ile Ile Ile Ile His Leu Val Glu Val Val Pro Asn195 200 205 gga gat ctg gtg cgg cgg gat cct atg cat att ttt cat cat aacaca 672 Gly Asp Leu Val Arg Arg Asp Pro Met His Ile Phe His His Asn Thr210 215 220 cat atg tgg aca atg cag tgg gaa ctg tca cca ccc tta ccc ctgtgt 720 His Met Trp Thr Met Gln Trp Glu Leu Ser Pro Pro Leu Pro Leu Cys225 230 235 240 gca cac gag gga aag atg gac cct cat gcc agt gaa gtg ataagt tgc 768 Ala His Glu Gly Lys Met Asp Pro His Ala Ser Glu Val Ile SerCys 245 250 255 aag gtt cta cac ttt tta cat cag tac atg atg tct tgc aactac ttc 816 Lys Val Leu His Phe Leu His Gln Tyr Met Met Ser Cys Asn TyrPhe 260 265 270 tgg atg ctc tgc gag ggg atc tat ctt cat act ctg att gtcatg gct 864 Trp Met Leu Cys Glu Gly Ile Tyr Leu His Thr Leu Ile Val MetAla 275 280 285 gtg ttt acc gac gag caa cgc cta cgc tgg tac tat ctt cttggc tgg 912 Val Phe Thr Asp Glu Gln Arg Leu Arg Trp Tyr Tyr Leu Leu GlyTrp 290 295 300 ggg ttc ccg ata gtg cca acc att atc cac gcc atc act cgtgcc ctc 960 Gly Phe Pro Ile Val Pro Thr Ile Ile His Ala Ile Thr Arg AlaLeu 305 310 315 320 tac tac aac gac aac tgc tgg ctg agt gca gaa acc cacttg ctt tac 1008 Tyr Tyr Asn Asp Asn Cys Trp Leu Ser Ala Glu Thr His LeuLeu Tyr 325 330 335 atc atc cat gga ccc gtc atg gtg gct ctg gtg gtc aacttc ttc ttt 1056 Ile Ile His Gly Pro Val Met Val Ala Leu Val Val Asn PhePhe Phe 340 345 350 ctt ctc aac att gtc cgc gtg ctt gtg acc aag atg aggcaa acc cac 1104 Leu Leu Asn Ile Val Arg Val Leu Val Thr Lys Met Arg GlnThr His 355 360 365 gag gcc gag tcc tac atg tac ctg aag gct gtg aag gccacc atg gtc 1152 Glu Ala Glu Ser Tyr Met Tyr Leu Lys Ala Val Lys Ala ThrMet Val 370 375 380 ctt gtg ccc ctg ctg ggg atc cag ttt gtt gtg ttt ccctgg agg ccc 1200 Leu Val Pro Leu Leu Gly Ile Gln Phe Val Val Phe Pro TrpArg Pro 385 390 395 400 tcc aac aag gtg ctt ggg aag atc tat gat tat ctcatg cac tct ctg 1248 Ser Asn Lys Val Leu Gly Lys Ile Tyr Asp Tyr Leu MetHis Ser Leu 405 410 415 att cat ttc cag gga ttc ttt gtg gcg act atc tactgc ttc tgc aac 1296 Ile His Phe Gln Gly Phe Phe Val Ala Thr Ile Tyr CysPhe Cys Asn 420 425 430 cat gag gtg caa gtc acc ctg aag cgc cag tgg acgcag ttc aag atc 1344 His Glu Val Gln Val Thr Leu Lys Arg Gln Trp Thr GlnPhe Lys Ile 435 440 445 cag tgg agc caa cgc tgg gga agg cgc cgc ccc accaac cgc gta gtt 1392 Gln Trp Ser Gln Arg Trp Gly Arg Arg Arg Pro Thr AsnArg Val Val 450 455 460 agt gct cct cgg gct gta gcc ttc gct gag cca gatggc ctc ccc att 1440 Ser Ala Pro Arg Ala Val Ala Phe Ala Glu Pro Asp GlyLeu Pro Ile 465 470 475 480 tac atc tgc cat cag gaa cca cgg aat cct ccaatc agc aac aac gaa 1488 Tyr Ile Cys His Gln Glu Pro Arg Asn Pro Pro IleSer Asn Asn Glu 485 490 495 ggc gag gag agt act gaa atg atc ccc atg aacgtc atc cag caa gac 1536 Gly Glu Glu Ser Thr Glu Met Ile Pro Met Asn ValIle Gln Gln Asp 500 505 510 gca tcc gct tga 1548 Ala Ser Ala 515 44 515PRT Mus musculus 44 Met Arg Phe Leu Leu Val Asn Arg Phe Thr Leu Leu LeuLeu Leu Leu 1 5 10 15 Val Ser Pro Thr Pro Val Leu Gln Ala Pro Thr AsnLeu Thr Asp Ser 20 25 30 Gly Leu Asp Gln Glu Pro Phe Leu Tyr Leu Val GlyArg Lys Lys Leu 35 40 45 Leu Asp Ala Gln Tyr Lys Cys Tyr Asp Arg Ile HisGln Leu Pro Ser 50 55 60 Tyr Glu Gly Glu Gly Leu Tyr Cys Asn Arg Thr TrpAsp Gly Trp Met 65 70 75 80 Cys Trp Asp Asp Thr Pro Ala Gly Ala Thr AlaTyr Gln His Cys Pro 85 90 95 Asp Tyr Phe Pro Asp Phe Asp Thr Ala Glu LysVal Ser Lys Tyr Cys 100 105 110 Asp Glu Asn Gly Glu Trp Phe Arg His ProAsp Ser Asn Arg Thr Trp 115 120 125 Ser Asn Tyr Thr Leu Cys Asn Ala PheThr Ser Glu Lys Leu Gln Asn 130 135 140 Ala Tyr Val Leu Tyr Tyr Leu AlaLeu Val Gly His Ser Leu Ser Ile 145 150 155 160 Ala Ala Leu Val Ala SerMet Leu Ile Phe Trp Ile Phe Lys Asn Leu 165 170 175 Ser Cys Gln Arg ValThr Leu His Lys His Met Phe Leu Thr Tyr Ile 180 185 190 Leu Asn Ser IleIle Ile Ile Ile His Leu Val Glu Val Val Pro Asn 195 200 205 Gly Asp LeuVal Arg Arg Asp Pro Met His Ile Phe His His Asn Thr 210 215 220 His MetTrp Thr Met Gln Trp Glu Leu Ser Pro Pro Leu Pro Leu Cys 225 230 235 240Ala His Glu Gly Lys Met Asp Pro His Ala Ser Glu Val Ile Ser Cys 245 250255 Lys Val Leu His Phe Leu His Gln Tyr Met Met Ser Cys Asn Tyr Phe 260265 270 Trp Met Leu Cys Glu Gly Ile Tyr Leu His Thr Leu Ile Val Met Ala275 280 285 Val Phe Thr Asp Glu Gln Arg Leu Arg Trp Tyr Tyr Leu Leu GlyTrp 290 295 300 Gly Phe Pro Ile Val Pro Thr Ile Ile His Ala Ile Thr ArgAla Leu 305 310 315 320 Tyr Tyr Asn Asp Asn Cys Trp Leu Ser Ala Glu ThrHis Leu Leu Tyr 325 330 335 Ile Ile His Gly Pro Val Met Val Ala Leu ValVal Asn Phe Phe Phe 340 345 350 Leu Leu Asn Ile Val Arg Val Leu Val ThrLys Met Arg Gln Thr His 355 360 365 Glu Ala Glu Ser Tyr Met Tyr Leu LysAla Val Lys Ala Thr Met Val 370 375 380 Leu Val Pro Leu Leu Gly Ile GlnPhe Val Val Phe Pro Trp Arg Pro 385 390 395 400 Ser Asn Lys Val Leu GlyLys Ile Tyr Asp Tyr Leu Met His Ser Leu 405 410 415 Ile His Phe Gln GlyPhe Phe Val Ala Thr Ile Tyr Cys Phe Cys Asn 420 425 430 His Glu Val GlnVal Thr Leu Lys Arg Gln Trp Thr Gln Phe Lys Ile 435 440 445 Gln Trp SerGln Arg Trp Gly Arg Arg Arg Pro Thr Asn Arg Val Val 450 455 460 Ser AlaPro Arg Ala Val Ala Phe Ala Glu Pro Asp Gly Leu Pro Ile 465 470 475 480Tyr Ile Cys His Gln Glu Pro Arg Asn Pro Pro Ile Ser Asn Asn Glu 485 490495 Gly Glu Glu Ser Thr Glu Met Ile Pro Met Asn Val Ile Gln Gln Asp 500505 510 Ala Ser Ala 515 45 800 DNA Homo sapiens CDS (33)..(479) 45cgagcggact cgactcggca ccgctgtgca cc atg gcc cgg gcc ctg tgc cgc 53 MetAla Arg Ala Leu Cys Arg 1 5 ctc ccg cgg cgc ggc ctc tgg ctg ctc ctg gcccat cac ctc ttc atg 101 Leu Pro Arg Arg Gly Leu Trp Leu Leu Leu Ala HisHis Leu Phe Met 10 15 20 acc act gcc tgc cag gag gct aac tac ggt gcc ctcctc cgg gag ctc 149 Thr Thr Ala Cys Gln Glu Ala Asn Tyr Gly Ala Leu LeuArg Glu Leu 25 30 35 tgc ctc acc cag ttc cag gta gac atg gag gcc gtc ggggag acg ctg 197 Cys Leu Thr Gln Phe Gln Val Asp Met Glu Ala Val Gly GluThr Leu 40 45 50 55 tgg tgt gac tgg ggc agg acc atc agg agc tac agg gagctg gcc gac 245 Trp Cys Asp Trp Gly Arg Thr Ile Arg Ser Tyr Arg Glu LeuAla Asp 60 65 70 tgc acc tgg cac atg gcg gag aag ctg ggc tgc ttc tgg cccaat gca 293 Cys Thr Trp His Met Ala Glu Lys Leu Gly Cys Phe Trp Pro AsnAla 75 80 85 gag gtg gac agg ttc ttc ctg gca gtg cat ggc cgc tac ttc aggagc 341 Glu Val Asp Arg Phe Phe Leu Ala Val His Gly Arg Tyr Phe Arg Ser90 95 100 tgc ccc atc tca ggc agg gcc gtg cgg gac ccg ccc ggc agc atcctc 389 Cys Pro Ile Ser Gly Arg Ala Val Arg Asp Pro Pro Gly Ser Ile Leu105 110 115 tac ccc ttc atc gtg gtc ccc atc acg gtg acc ctg ctg gtg acggca 437 Tyr Pro Phe Ile Val Val Pro Ile Thr Val Thr Leu Leu Val Thr Ala120 125 130 135 ctg gtg gtc tgg cag agc aag cgc act gag ggc att gtg tag479 Leu Val Val Trp Gln Ser Lys Arg Thr Glu Gly Ile Val 140 145gcggggccca ggctgcccgc gggtgcaccc aggctgcagg gtgaggccag gcaggcctgg 539gtaggggcag cttctggagc cttgggacag agcaggccca caatgccccc cttcttccag 599ccaagaagag ctcacaggag tccagagtag ccgaggctct ggtattaacc tggaagcccc 659cctggctgga ggccaccgcc accctaggaa gggggcaggg acgtgacctt gacttacctc 719tggaaagggt cccagcctag actgcttacc ccatagccac atttgtggat gagtggtttg 779tgattaaaag ggatgttctt g 800 46 148 PRT Homo sapiens 46 Met Ala Arg AlaLeu Cys Arg Leu Pro Arg Arg Gly Leu Trp Leu Leu 1 5 10 15 Leu Ala HisHis Leu Phe Met Thr Thr Ala Cys Gln Glu Ala Asn Tyr 20 25 30 Gly Ala LeuLeu Arg Glu Leu Cys Leu Thr Gln Phe Gln Val Asp Met 35 40 45 Glu Ala ValGly Glu Thr Leu Trp Cys Asp Trp Gly Arg Thr Ile Arg 50 55 60 Ser Tyr ArgGlu Leu Ala Asp Cys Thr Trp His Met Ala Glu Lys Leu 65 70 75 80 Gly CysPhe Trp Pro Asn Ala Glu Val Asp Arg Phe Phe Leu Ala Val 85 90 95 His GlyArg Tyr Phe Arg Ser Cys Pro Ile Ser Gly Arg Ala Val Arg 100 105 110 AspPro Pro Gly Ser Ile Leu Tyr Pro Phe Ile Val Val Pro Ile Thr 115 120 125Val Thr Leu Leu Val Thr Ala Leu Val Val Trp Gln Ser Lys Arg Thr 130 135140 Glu Gly Ile Val 145 47 825 DNA Homo sapiens CDS (34)..(480) 47ggcacgaggc tcgactcggc accgctgtgc acc atg gcc cgg gcc ctg tgc cgc 54 MetAla Arg Ala Leu Cys Arg 1 5 ctc ccg cgg cgc ggc ctc tgg ctg ctc ctg gcccat cac ctc ttc atg 102 Leu Pro Arg Arg Gly Leu Trp Leu Leu Leu Ala HisHis Leu Phe Met 10 15 20 acc act gcc tgc cag gag gct aac tac ggt gcc ctcctc cgg gag ctc 150 Thr Thr Ala Cys Gln Glu Ala Asn Tyr Gly Ala Leu LeuArg Glu Leu 25 30 35 tgc ctc acc cag ttc cag gta gac atg gag gcc gtc ggggag acg ctg 198 Cys Leu Thr Gln Phe Gln Val Asp Met Glu Ala Val Gly GluThr Leu 40 45 50 55 tgg tgt gac tgg ggc agg acc atc agg agc tac agg gagctg gcc gac 246 Trp Cys Asp Trp Gly Arg Thr Ile Arg Ser Tyr Arg Glu LeuAla Asp 60 65 70 tgc acc tgg cac atg gcg gag aag ctg ggc tgc ttc tgg cccaat gca 294 Cys Thr Trp His Met Ala Glu Lys Leu Gly Cys Phe Trp Pro AsnAla 75 80 85 gag gtg gac agg ttc ttc ctg gca gtg cat ggc cgc tac ttc aggagc 342 Glu Val Asp Arg Phe Phe Leu Ala Val His Gly Arg Tyr Phe Arg Ser90 95 100 tgc ccc atc tca ggc agg gcc gtg cgg gac ccg ccc ggc agc atcctc 390 Cys Pro Ile Ser Gly Arg Ala Val Arg Asp Pro Pro Gly Ser Ile Leu105 110 115 tac ccc ttc atc gtg gtc ccc atc acg gtg acc ctg ctg gtg acggca 438 Tyr Pro Phe Ile Val Val Pro Ile Thr Val Thr Leu Leu Val Thr Ala120 125 130 135 ctg gtg gtc tgg cag agc aag cgc act gag ggc att gtg tag480 Leu Val Val Trp Gln Ser Lys Arg Thr Glu Gly Ile Val 140 145gcggggccca ggctgcccgc gggtgcaccc aggctgcagg gtgaggccag gcaggcctgg 540gtaggggcag cttctggagc cttgggacag agcaggccca caatgccccc cttcttccag 600ccaagaagag ctcacaggag tccagagtag ccgaggctct ggtattaacc tggaagcccc 660cctggctgga ggccaccgcc accctaggaa gggggcaggg acgtgacctt gacttacctc 720tggaaagggt cccagcctag actgcctacc ccatagccac atttgtggat gagtggtttg 780tgattaaaag ggatgttctt gaacttgaaa aaaaaaaaaa aaaaa 825 48 148 PRT Homosapiens 48 Met Ala Arg Ala Leu Cys Arg Leu Pro Arg Arg Gly Leu Trp LeuLeu 1 5 10 15 Leu Ala His His Leu Phe Met Thr Thr Ala Cys Gln Glu AlaAsn Tyr 20 25 30 Gly Ala Leu Leu Arg Glu Leu Cys Leu Thr Gln Phe Gln ValAsp Met 35 40 45 Glu Ala Val Gly Glu Thr Leu Trp Cys Asp Trp Gly Arg ThrIle Arg 50 55 60 Ser Tyr Arg Glu Leu Ala Asp Cys Thr Trp His Met Ala GluLys Leu 65 70 75 80 Gly Cys Phe Trp Pro Asn Ala Glu Val Asp Arg Phe PheLeu Ala Val 85 90 95 His Gly Arg Tyr Phe Arg Ser Cys Pro Ile Ser Gly ArgAla Val Arg 100 105 110 Asp Pro Pro Gly Ser Ile Leu Tyr Pro Phe Ile ValVal Pro Ile Thr 115 120 125 Val Thr Leu Leu Val Thr Ala Leu Val Val TrpGln Ser Lys Arg Thr 130 135 140 Glu Gly Ile Val 145 49 549 DNA Rattusnorvegicus CDS (17)..(463) 49 cggggctctg cttgcc atg gcc ccc ggc ctg cggggc ctc ccg cgg cgc ggc 52 Met Ala Pro Gly Leu Arg Gly Leu Pro Arg ArgGly 1 5 10 ctc tgg ctg ctg ctg gct cat cat ctc ttc atg gtc act gcc tgccgg 100 Leu Trp Leu Leu Leu Ala His His Leu Phe Met Val Thr Ala Cys Arg15 20 25 gac cct gac tat ggt act ctc atc cag gag ctg tgt ctc agc cgc ttc148 Asp Pro Asp Tyr Gly Thr Leu Ile Gln Glu Leu Cys Leu Ser Arg Phe 3035 40 aaa gag gac atg gag acc ata ggg aag act ctg tgg tgt gac tgg gga196 Lys Glu Asp Met Glu Thr Ile Gly Lys Thr Leu Trp Cys Asp Trp Gly 4550 55 60 aag acc ata ggg agc tat ggg gag ctc act cac tgc acc aaa ctc gtg244 Lys Thr Ile Gly Ser Tyr Gly Glu Leu Thr His Cys Thr Lys Leu Val 6570 75 gca aac aag att ggc tgt ttc tgg ccc aat ccg gaa gtg gac aag ttc292 Ala Asn Lys Ile Gly Cys Phe Trp Pro Asn Pro Glu Val Asp Lys Phe 8085 90 ttc att gct gtc cac cac cgc tac ttc agc aag tgc cca gtc tcg ggc340 Phe Ile Ala Val His His Arg Tyr Phe Ser Lys Cys Pro Val Ser Gly 95100 105 agg gcc ctg cgg gac cct ccc aac agc atc ctc tgc cct ttc att gtg388 Arg Ala Leu Arg Asp Pro Pro Asn Ser Ile Leu Cys Pro Phe Ile Val 110115 120 ctc ccc att acg gtc aca ctg ctc atg act gcc ctg gtg gtc tgg agg436 Leu Pro Ile Thr Val Thr Leu Leu Met Thr Ala Leu Val Val Trp Arg 125130 135 140 agc aag cgc aca gag ggc atc gtg tag gtgtcccagg tgatggggga483 Ser Lys Arg Thr Glu Gly Ile Val 145 ttggggaacc atgggcctgg cccagcaacagcatcaggga cagaccccac attgcatcct 543 gctcta 549 50 148 PRT Rattusnorvegicus 50 Met Ala Pro Gly Leu Arg Gly Leu Pro Arg Arg Gly Leu TrpLeu Leu 1 5 10 15 Leu Ala His His Leu Phe Met Val Thr Ala Cys Arg AspPro Asp Tyr 20 25 30 Gly Thr Leu Ile Gln Glu Leu Cys Leu Ser Arg Phe LysGlu Asp Met 35 40 45 Glu Thr Ile Gly Lys Thr Leu Trp Cys Asp Trp Gly LysThr Ile Gly 50 55 60 Ser Tyr Gly Glu Leu Thr His Cys Thr Lys Leu Val AlaAsn Lys Ile 65 70 75 80 Gly Cys Phe Trp Pro Asn Pro Glu Val Asp Lys PhePhe Ile Ala Val 85 90 95 His His Arg Tyr Phe Ser Lys Cys Pro Val Ser GlyArg Ala Leu Arg 100 105 110 Asp Pro Pro Asn Ser Ile Leu Cys Pro Phe IleVal Leu Pro Ile Thr 115 120 125 Val Thr Leu Leu Met Thr Ala Leu Val ValTrp Arg Ser Lys Arg Thr 130 135 140 Glu Gly Ile Val 145 51 472 DNARattus norvegicus CDS (16)..(462) 51 ggggctctgc ttgcc atg gcc ctc ggcctg cgg ggc ctc ccg cgg cgc ggc 51 Met Ala Leu Gly Leu Arg Gly Leu ProArg Arg Gly 1 5 10 ctc tgg ctg ctg ctg gtt cat cat ctc ttc atg gtc actgcc tgc cgg 99 Leu Trp Leu Leu Leu Val His His Leu Phe Met Val Thr AlaCys Arg 15 20 25 gac cct gac tat ggt act ctc atc cag gag ctg tgt ctc agccgc ttc 147 Asp Pro Asp Tyr Gly Thr Leu Ile Gln Glu Leu Cys Leu Ser ArgPhe 30 35 40 aaa gag gac atg gag acc ata ggg aag act ctg tgg tgt gac tgggga 195 Lys Glu Asp Met Glu Thr Ile Gly Lys Thr Leu Trp Cys Asp Trp Gly45 50 55 60 aag acc ata ggg agc tat ggg gag ctc act cac tgc acc aaa ctcgtg 243 Lys Thr Ile Gly Ser Tyr Gly Glu Leu Thr His Cys Thr Lys Leu Val65 70 75 gca aac aag att ggc tgt ttc tgg ccc aat ccg gaa gtg gac aag ttc291 Ala Asn Lys Ile Gly Cys Phe Trp Pro Asn Pro Glu Val Asp Lys Phe 8085 90 ttc att gct gtc cac cac cgc tac ttc agc aag tgc cca gtc tcg ggc339 Phe Ile Ala Val His His Arg Tyr Phe Ser Lys Cys Pro Val Ser Gly 95100 105 agg gcc ctg cgg gac cct ccc aac agc atc ctc tgc cct ttc att gtg387 Arg Ala Leu Arg Asp Pro Pro Asn Ser Ile Leu Cys Pro Phe Ile Val 110115 120 ctc ccc att acg gtc aca ctg ctc atg act gcc ctg gtg gtc tgg agg435 Leu Pro Ile Thr Val Thr Leu Leu Met Thr Ala Leu Val Val Trp Arg 125130 135 140 agc aag cgc aca gag ggc atc gtg tag gtgtcccagg 472 Ser LysArg Thr Glu Gly Ile Val 145 52 148 PRT Rattus norvegicus 52 Met Ala LeuGly Leu Arg Gly Leu Pro Arg Arg Gly Leu Trp Leu Leu 1 5 10 15 Leu ValHis His Leu Phe Met Val Thr Ala Cys Arg Asp Pro Asp Tyr 20 25 30 Gly ThrLeu Ile Gln Glu Leu Cys Leu Ser Arg Phe Lys Glu Asp Met 35 40 45 Glu ThrIle Gly Lys Thr Leu Trp Cys Asp Trp Gly Lys Thr Ile Gly 50 55 60 Ser TyrGly Glu Leu Thr His Cys Thr Lys Leu Val Ala Asn Lys Ile 65 70 75 80 GlyCys Phe Trp Pro Asn Pro Glu Val Asp Lys Phe Phe Ile Ala Val 85 90 95 HisHis Arg Tyr Phe Ser Lys Cys Pro Val Ser Gly Arg Ala Leu Arg 100 105 110Asp Pro Pro Asn Ser Ile Leu Cys Pro Phe Ile Val Leu Pro Ile Thr 115 120125 Val Thr Leu Leu Met Thr Ala Leu Val Val Trp Arg Ser Lys Arg Thr 130135 140 Glu Gly Ile Val 145 53 993 DNA Mus musculus CDS (34)..(558) 53tgagcggata acaatttcac acaggacaca gct atg acc ttg att acg cca agc 54 MetThr Leu Ile Thr Pro Ser 1 5 tcg aaa tta acc ctc act aaa ggg aac aaa agctgg agc tcg cgc gcc 102 Ser Lys Leu Thr Leu Thr Lys Gly Asn Lys Ser TrpSer Ser Arg Ala 10 15 20 tgc agg tcg aca cta gtg gat cca aag aat tcg gcacga gtg ggg ctc 150 Cys Arg Ser Thr Leu Val Asp Pro Lys Asn Ser Ala ArgVal Gly Leu 25 30 35 tgc ttg cca tgg ccc cgg gcc tgc ggg gcc tcc cgc ggtgcg gcc tct 198 Cys Leu Pro Trp Pro Arg Ala Cys Gly Ala Ser Arg Gly AlaAla Ser 40 45 50 55 ggc tgc tgc tgg ctc acc atc tct tca tgg tca ctg cctgcc ggg acc 246 Gly Cys Cys Trp Leu Thr Ile Ser Ser Trp Ser Leu Pro AlaGly Thr 60 65 70 ctg act atg gga ctc tca tcc agg agc tgt gcc tca gcc gcttca agg 294 Leu Thr Met Gly Leu Ser Ser Arg Ser Cys Ala Ser Ala Ala SerArg 75 80 85 aga aca tgg aga cta ttg gga aga cgc tat ggt gtg act ggg gaaaga 342 Arg Thr Trp Arg Leu Leu Gly Arg Arg Tyr Gly Val Thr Gly Glu Arg90 95 100 cca tac aga gct atg ggg agc tca ctt act gca cca agc acg tggcgc 390 Pro Tyr Arg Ala Met Gly Ser Ser Leu Thr Ala Pro Ser Thr Trp Arg105 110 115 aca cga ttg gct gtt tct ggc cca atc cgg aag tgg aca gat tcttca 438 Thr Arg Leu Ala Val Ser Gly Pro Ile Arg Lys Trp Thr Asp Ser Ser120 125 130 135 tcg ctg tcc acc atc gat act tca gca agt gcc cca tct cgggca ggg 486 Ser Leu Ser Thr Ile Asp Thr Ser Ala Ser Ala Pro Ser Arg AlaGly 140 145 150 ccc tgc ggg acc ctc cca aca gca tcc tct gcc ctt tca ttgcgc tcc 534 Pro Cys Gly Thr Leu Pro Thr Ala Ser Ser Ala Leu Ser Leu ArgSer 155 160 165 cca tta cgg tca cgc tgc tca tga ctgcactggt ggtctggaggagcaagcgca 588 Pro Leu Arg Ser Arg Cys Ser 170 cagagggcat cgtgtaggtatcccaggtga tgagggattg gggaaccatg ggcctagccc 648 agcaacagca tcaggagcaggtcccacctt gcatcctgct ctagcctagt tagcacagga 708 cttgagagtg gctctgcattaagctgaata tgccctagcc agaggcttct agcaggggag 768 caggggcctg cctctgcttacctctgagat tgttctaagc accaggtctc tggtacactt 828 catcaccact gtgggcattctgaactccaa ggaagactgc acagatgtgt ttgtagatgc 888 acagtttgtg attaaaagagtattcttaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 948 aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaa 993 54 174 PRT Mus musculus 54 Met Thr LeuIle Thr Pro Ser Ser Lys Leu Thr Leu Thr Lys Gly Asn 1 5 10 15 Lys SerTrp Ser Ser Arg Ala Cys Arg Ser Thr Leu Val Asp Pro Lys 20 25 30 Asn SerAla Arg Val Gly Leu Cys Leu Pro Trp Pro Arg Ala Cys Gly 35 40 45 Ala SerArg Gly Ala Ala Ser Gly Cys Cys Trp Leu Thr Ile Ser Ser 50 55 60 Trp SerLeu Pro Ala Gly Thr Leu Thr Met Gly Leu Ser Ser Arg Ser 65 70 75 80 CysAla Ser Ala Ala Ser Arg Arg Thr Trp Arg Leu Leu Gly Arg Arg 85 90 95 TyrGly Val Thr Gly Glu Arg Pro Tyr Arg Ala Met Gly Ser Ser Leu 100 105 110Thr Ala Pro Ser Thr Trp Arg Thr Arg Leu Ala Val Ser Gly Pro Ile 115 120125 Arg Lys Trp Thr Asp Ser Ser Ser Leu Ser Thr Ile Asp Thr Ser Ala 130135 140 Ser Ala Pro Ser Arg Ala Gly Pro Cys Gly Thr Leu Pro Thr Ala Ser145 150 155 160 Ser Ala Leu Ser Leu Arg Ser Pro Leu Arg Ser Arg Cys Ser165 170 55 844 DNA Mus musculus CDS (60)..(506) 55 ggcacgagga gcgggcgcagagctcggcaa ggcgctggga cggtggggct ctgcttgcc 59 atg gcc ccg ggc ctg cggggc ctc ccg cgg tgc ggc ctc tgg ctg ctg 107 Met Ala Pro Gly Leu Arg GlyLeu Pro Arg Cys Gly Leu Trp Leu Leu 1 5 10 15 ctg gct cac cat ctc ttcatg gtc act gcc tgc cgg gac cct gac tat 155 Leu Ala His His Leu Phe MetVal Thr Ala Cys Arg Asp Pro Asp Tyr 20 25 30 ggg act ctc atc cag gag ctgtgc ctc agc cgc ttc aag gag aac atg 203 Gly Thr Leu Ile Gln Glu Leu CysLeu Ser Arg Phe Lys Glu Asn Met 35 40 45 gag act att ggg aag acg cta tggtgt gac tgg gga aag acc ata cag 251 Glu Thr Ile Gly Lys Thr Leu Trp CysAsp Trp Gly Lys Thr Ile Gln 50 55 60 agc tat ggg gag ctc act tac tgc accaag cac gtg gcg cac acg att 299 Ser Tyr Gly Glu Leu Thr Tyr Cys Thr LysHis Val Ala His Thr Ile 65 70 75 80 ggc tgt ttc tgg ccc aat ccg gaa gtggac aga ttc ttc atc gct gtc 347 Gly Cys Phe Trp Pro Asn Pro Glu Val AspArg Phe Phe Ile Ala Val 85 90 95 cac cat cga tac ttc agc aag tgc ccc atctcg ggc agg gcc ctg cgg 395 His His Arg Tyr Phe Ser Lys Cys Pro Ile SerGly Arg Ala Leu Arg 100 105 110 gac cct ccc aac agc atc ctc tgc cct ttcatt gcg ctc ccc att acg 443 Asp Pro Pro Asn Ser Ile Leu Cys Pro Phe IleAla Leu Pro Ile Thr 115 120 125 gtc acg ctg ctc atg act gca ctg gtg gtctgg agg agc aag cgc aca 491 Val Thr Leu Leu Met Thr Ala Leu Val Val TrpArg Ser Lys Arg Thr 130 135 140 gag ggc atc gtg tag gtatcccaggtgatgaggga ttggggaacc atgggcctag 546 Glu Gly Ile Val 145 cccagcaacagcatcaggag caggtcccac cttgcatcct gctctagcct agttagcaca 606 ggacttgagagtggctctgc attaagctga atatgcccta gccagaggct tctagcaggg 666 gagcaggggcctgcctctgc ttacctctga gattgttcta agcaccaggt ctctggtaca 726 cttcatcaccactgtgggca ttctgaactc caaggaagac tgcacagatg tgtttgtaga 786 tgcacagtttgtgattaaaa gagtattctt aaacctggaa aaaaaaaaaa aaaaaaaa 844 56 148 PRT Musmusculus 56 Met Ala Pro Gly Leu Arg Gly Leu Pro Arg Cys Gly Leu Trp LeuLeu 1 5 10 15 Leu Ala His His Leu Phe Met Val Thr Ala Cys Arg Asp ProAsp Tyr 20 25 30 Gly Thr Leu Ile Gln Glu Leu Cys Leu Ser Arg Phe Lys GluAsn Met 35 40 45 Glu Thr Ile Gly Lys Thr Leu Trp Cys Asp Trp Gly Lys ThrIle Gln 50 55 60 Ser Tyr Gly Glu Leu Thr Tyr Cys Thr Lys His Val Ala HisThr Ile 65 70 75 80 Gly Cys Phe Trp Pro Asn Pro Glu Val Asp Arg Phe PheIle Ala Val 85 90 95 His His Arg Tyr Phe Ser Lys Cys Pro Ile Ser Gly ArgAla Leu Arg 100 105 110 Asp Pro Pro Asn Ser Ile Leu Cys Pro Phe Ile AlaLeu Pro Ile Thr 115 120 125 Val Thr Leu Leu Met Thr Ala Leu Val Val TrpArg Ser Lys Arg Thr 130 135 140 Glu Gly Ile Val 145 57 798 DNA Musmusculus CDS (25)..(471) 57 ccacgcgtcc gggctctgct tgcc atg gcc ccg ggcctg cgg ggc ctc ccg 51 Met Ala Pro Gly Leu Arg Gly Leu Pro 1 5 cgg tgcggc ctc tgg ctg ctg ctg gct cac cat ctc ttc atg gtc act 99 Arg Cys GlyLeu Trp Leu Leu Leu Ala His His Leu Phe Met Val Thr 10 15 20 25 gcc tgccgg gac cct gac tat ggg act ctc atc cag gag ctg tgc ctc 147 Ala Cys ArgAsp Pro Asp Tyr Gly Thr Leu Ile Gln Glu Leu Cys Leu 30 35 40 agc cgc ttcaag gag aac atg gag act att ggg aag acg cta tgg tgt 195 Ser Arg Phe LysGlu Asn Met Glu Thr Ile Gly Lys Thr Leu Trp Cys 45 50 55 gac tgg gga aagacc ata cag agc tat ggg gag ctc act tac tgc acc 243 Asp Trp Gly Lys ThrIle Gln Ser Tyr Gly Glu Leu Thr Tyr Cys Thr 60 65 70 aag cac gtg gcg cacacg att ggc tgt ttc tgg ccc aat ccg gaa gtg 291 Lys His Val Ala His ThrIle Gly Cys Phe Trp Pro Asn Pro Glu Val 75 80 85 gac aga ttc ttc atc gctgtc cac cat cga tac ttc agc aag tgc ccc 339 Asp Arg Phe Phe Ile Ala ValHis His Arg Tyr Phe Ser Lys Cys Pro 90 95 100 105 atc tcg ggc agg gccctg cgg gac cct ccc aac agc atc ctc tgc cct 387 Ile Ser Gly Arg Ala LeuArg Asp Pro Pro Asn Ser Ile Leu Cys Pro 110 115 120 ttc att gcg ctc cccatt acg gtc acg ctg ctc atg act gca ctg gtg 435 Phe Ile Ala Leu Pro IleThr Val Thr Leu Leu Met Thr Ala Leu Val 125 130 135 gtc tgg agg agc aagcgc aca gag ggc atc gtg tag gtatcccagg 481 Val Trp Arg Ser Lys Arg ThrGlu Gly Ile Val 140 145 tgatgaggga ttggggaacc atgggcctag cccagcaacagcatcaggag caggtcccac 541 cttgcatcct gctctagcct agttagcaca ggacttgagagtggctctgc attaagctga 601 atatgcccta gccagaggct tctagcaggg gagcaggggcctgcctctgc ttacctctga 661 gattgttcta agcaccaggt ctctggtaca cttcatcaccactgtgggca ttctgaactc 721 caaggaagac tgcacagatg tgtttgtaga tgcacagtttgtgattaaaa gagtattctt 781 aaaaaaaaaa aaaaaaa 798 58 148 PRT Mus musculus58 Met Ala Pro Gly Leu Arg Gly Leu Pro Arg Cys Gly Leu Trp Leu Leu 1 510 15 Leu Ala His His Leu Phe Met Val Thr Ala Cys Arg Asp Pro Asp Tyr 2025 30 Gly Thr Leu Ile Gln Glu Leu Cys Leu Ser Arg Phe Lys Glu Asn Met 3540 45 Glu Thr Ile Gly Lys Thr Leu Trp Cys Asp Trp Gly Lys Thr Ile Gln 5055 60 Ser Tyr Gly Glu Leu Thr Tyr Cys Thr Lys His Val Ala His Thr Ile 6570 75 80 Gly Cys Phe Trp Pro Asn Pro Glu Val Asp Arg Phe Phe Ile Ala Val85 90 95 His His Arg Tyr Phe Ser Lys Cys Pro Ile Ser Gly Arg Ala Leu Arg100 105 110 Asp Pro Pro Asn Ser Ile Leu Cys Pro Phe Ile Ala Leu Pro IleThr 115 120 125 Val Thr Leu Leu Met Thr Ala Leu Val Val Trp Arg Ser LysArg Thr 130 135 140 Glu Gly Ile Val 145 59 240 DNA Sus scrofa CDS(1)..(240) 59 agg acc atc agg agc tat aaa gac ctc tca gac tgc acc aggctc gtg 48 Arg Thr Ile Arg Ser Tyr Lys Asp Leu Ser Asp Cys Thr Arg LeuVal 1 5 10 15 gcg caa agg ctg gac tgc ttc tgg ccc aac gcg gcg gtg gacaag ttc 96 Ala Gln Arg Leu Asp Cys Phe Trp Pro Asn Ala Ala Val Asp LysPhe 20 25 30 ttc ctg gga gtc cac cag cag tac ttc aga aac tgc ccc gtc tccggc 144 Phe Leu Gly Val His Gln Gln Tyr Phe Arg Asn Cys Pro Val Ser Gly35 40 45 agg gcc ttg cag gac ccg ccc agc agc gtc ctc tgc ccc ttc atc gtc192 Arg Ala Leu Gln Asp Pro Pro Ser Ser Val Leu Cys Pro Phe Ile Val 5055 60 gtc ccc atc ctg gcg acc ctg ctc atg acc gca ctg gtg gtc tgg cag240 Val Pro Ile Leu Ala Thr Leu Leu Met Thr Ala Leu Val Val Trp Gln 6570 75 80 60 80 PRT Sus scrofa 60 Arg Thr Ile Arg Ser Tyr Lys Asp Leu SerAsp Cys Thr Arg Leu Val 1 5 10 15 Ala Gln Arg Leu Asp Cys Phe Trp ProAsn Ala Ala Val Asp Lys Phe 20 25 30 Phe Leu Gly Val His Gln Gln Tyr PheArg Asn Cys Pro Val Ser Gly 35 40 45 Arg Ala Leu Gln Asp Pro Pro Ser SerVal Leu Cys Pro Phe Ile Val 50 55 60 Val Pro Ile Leu Ala Thr Leu Leu MetThr Ala Leu Val Val Trp Gln 65 70 75 80 61 1312 DNA Homo sapiens CDS(30)..(476) 61 gagcgtgacc cagctgcggc cggccagcc atg gag act gga gcg ctgcgg cgc 53 Met Glu Thr Gly Ala Leu Arg Arg 1 5 ccg caa ctt ctc ccg ttgctg ctg ctg ctc tgc ggt ggg tgt ccc aga 101 Pro Gln Leu Leu Pro Leu LeuLeu Leu Leu Cys Gly Gly Cys Pro Arg 10 15 20 gca ggc ggc tgc aac gag acaggc atg ttg gag agg ctg ccc ctg tgt 149 Ala Gly Gly Cys Asn Glu Thr GlyMet Leu Glu Arg Leu Pro Leu Cys 25 30 35 40 ggg aag gct ttc gca gac atgatg ggc aag gtg gac gtc tgg aag tgg 197 Gly Lys Ala Phe Ala Asp Met MetGly Lys Val Asp Val Trp Lys Trp 45 50 55 tgc aac ctg tcc gag ttc atc gtgtac tat gag agt ttc acc aac tgc 245 Cys Asn Leu Ser Glu Phe Ile Val TyrTyr Glu Ser Phe Thr Asn Cys 60 65 70 acc gag atg gag gcc aat gtc gtg ggctgc tac tgg ccc aac ccc ctg 293 Thr Glu Met Glu Ala Asn Val Val Gly CysTyr Trp Pro Asn Pro Leu 75 80 85 gcc cag ggc ttc atc acc ggc atc cac aggcag ttc ttc tcc aac tgc 341 Ala Gln Gly Phe Ile Thr Gly Ile His Arg GlnPhe Phe Ser Asn Cys 90 95 100 acc gtg gac agg gtc cac ttg gag gac ccccca gac gag gtt ctc atc 389 Thr Val Asp Arg Val His Leu Glu Asp Pro ProAsp Glu Val Leu Ile 105 110 115 120 ccg ctg atc gtt ata ccc gtc gtt ctgact gtc gcc atg gct ggc ctg 437 Pro Leu Ile Val Ile Pro Val Val Leu ThrVal Ala Met Ala Gly Leu 125 130 135 gtg gtg tgg cgc agc aaa cgc acc gacacg ctg ctg tga gggtcccggt 486 Val Val Trp Arg Ser Lys Arg Thr Asp ThrLeu Leu 140 145 gagatggagt gggtcacacc tggcaagctg gaagaaagtt ccctggggatgggagatcgg 546 gtgggtgctg ccaatctcca gctactgtgg ccacacccca cctggtcatgggcagacccc 606 tcccttcctg ggctgacctg ctccctcgag gccagcctgc tccctggctgaggctcaggc 666 tatccgccca agctctttgc tcattctagg gccagtggag gaaaatgtgataaggccaga 726 gcttgtgtgc tgggcaagaa atcacctgct gcatcctgtg ctccgcaggctgggccggaa 786 gcctctgcct gcaggtttct atgctgtttc ttagcacaga atccagcctagccttagccg 846 cagtctaggc cctgcttgga ctaggactcc ttgcttgacc ccatctctggttcctgccct 906 ggctcctgca ccagccccag ctcctgccta catccaggca gaaatataggcaggggctct 966 tggaagacgt tccgtgctgt gacctccgag ccctcctggt gggaagacagctggaaaggc 1026 tgggaggaga agggaggggc tgggggttcc caggagccat gcgtggcctgcagagtccat 1086 tccatcatga tgctgtgccc gctatgggct gtgtccatga ccagaggctggagtgggggt 1146 gtgttatagc ccctcaccgg gacttgctgt gcggatgggg cctgggcctccttcctacag 1206 gggctcctct gtgggtgagg ggccctctgg aatggcatcc catgagcttgtggcctctat 1266 ctgctaccat ctgtgtttta tctgagtaaa gttaccttac ttctgg 131262 148 PRT Homo sapiens 62 Met Glu Thr Gly Ala Leu Arg Arg Pro Gln LeuLeu Pro Leu Leu Leu 1 5 10 15 Leu Leu Cys Gly Gly Cys Pro Arg Ala GlyGly Cys Asn Glu Thr Gly 20 25 30 Met Leu Glu Arg Leu Pro Leu Cys Gly LysAla Phe Ala Asp Met Met 35 40 45 Gly Lys Val Asp Val Trp Lys Trp Cys AsnLeu Ser Glu Phe Ile Val 50 55 60 Tyr Tyr Glu Ser Phe Thr Asn Cys Thr GluMet Glu Ala Asn Val Val 65 70 75 80 Gly Cys Tyr Trp Pro Asn Pro Leu AlaGln Gly Phe Ile Thr Gly Ile 85 90 95 His Arg Gln Phe Phe Ser Asn Cys ThrVal Asp Arg Val His Leu Glu 100 105 110 Asp Pro Pro Asp Glu Val Leu IlePro Leu Ile Val Ile Pro Val Val 115 120 125 Leu Thr Val Ala Met Ala GlyLeu Val Val Trp Arg Ser Lys Arg Thr 130 135 140 Asp Thr Leu Leu 145 631191 DNA Mus musculus CDS (1)..(444) 63 atg aag acc cca gca cag cgg ctgcac ctt ctt cca ctg ttg ttg ctg 48 Met Lys Thr Pro Ala Gln Arg Leu HisLeu Leu Pro Leu Leu Leu Leu 1 5 10 15 ctt tgt ggt gag tgt gcc cag gtatgc ggc tgc aac gag aca ggg atg 96 Leu Cys Gly Glu Cys Ala Gln Val CysGly Cys Asn Glu Thr Gly Met 20 25 30 ctg gag agg ctg cct cgc tgt ggg aaagcc ttc gct gac atg atg cag 144 Leu Glu Arg Leu Pro Arg Cys Gly Lys AlaPhe Ala Asp Met Met Gln 35 40 45 aag gtg gct gtc tgg aag tgg tgc aac ctgtcg gag ttc atc gtg tat 192 Lys Val Ala Val Trp Lys Trp Cys Asn Leu SerGlu Phe Ile Val Tyr 50 55 60 tat gaa agc ttc act aac tgc acc gag atg gagacc aac atc atg ggc 240 Tyr Glu Ser Phe Thr Asn Cys Thr Glu Met Glu ThrAsn Ile Met Gly 65 70 75 80 tgc tac tgg ccc aac ccg ctg gcc cag agc ttcatc act gga atc cac 288 Cys Tyr Trp Pro Asn Pro Leu Ala Gln Ser Phe IleThr Gly Ile His 85 90 95 agg cag ttc ttt tcc aac tgc acg gtg gac agg acccac tgg gaa gac 336 Arg Gln Phe Phe Ser Asn Cys Thr Val Asp Arg Thr HisTrp Glu Asp 100 105 110 ccc ccg gat gaa gta ctc atc cca ctg atc gcg gttcct gtc gtg ctg 384 Pro Pro Asp Glu Val Leu Ile Pro Leu Ile Ala Val ProVal Val Leu 115 120 125 act gtg gct atg gct ggc ctg gtg gtg tgg cgc agcaag cac act gat 432 Thr Val Ala Met Ala Gly Leu Val Val Trp Arg Ser LysHis Thr Asp 130 135 140 cgg ctg ctg tga ggatctgctg gatggagggc catgcctggcaggctgggag 484 Arg Leu Leu 145 aatgttgctc agagctctga gagctggcagactcggcttc tgtctggttt gctttggcca 544 caccctacct ggccatgcca aagtcctcctgaccaggctg gtgtggccct tgctgtctag 604 cctgccgcct gctggggttc agattgtccatactttgctc tttcttgggc tagtggaaga 664 aagtgacaaa tcccaagttt gtggaccaggcatggaaatc aactgttgct gagccccgct 724 ccccaggctc ggttccctag tttctagccgtttcttggca gagtcttgct cagcctgaac 784 cccgccccag gtcctgaccc atttctagtcctgaccctga cccctgctac acttggccag 844 agagggcagg caaggtcatc tggaagatgtggacgccccc ccgcctctgt tcaagagact 904 gagcacatca tttatcagac atgaaggatagcctggggtc attaggagcc acgtgtgacc 964 tactgaccca cctgcctgtc ctctctgtgatctgtcacga ttctgtgtcc agtgtgggct 1024 ggagctgtgg cttgtttagc ccttcaaagacacctaccct gcaggtagag cgtgaacctc 1084 cttcttgagg ggtattcctg ggagtggggcgcactgagtg tgctcaaggg ttctgtctgc 1144 tgatgtcagt tctttttgat taaagtgtctccttacacgt ggaaaaa 1191 64 147 PRT Mus musculus 64 Met Lys Thr Pro AlaGln Arg Leu His Leu Leu Pro Leu Leu Leu Leu 1 5 10 15 Leu Cys Gly GluCys Ala Gln Val Cys Gly Cys Asn Glu Thr Gly Met 20 25 30 Leu Glu Arg LeuPro Arg Cys Gly Lys Ala Phe Ala Asp Met Met Gln 35 40 45 Lys Val Ala ValTrp Lys Trp Cys Asn Leu Ser Glu Phe Ile Val Tyr 50 55 60 Tyr Glu Ser PheThr Asn Cys Thr Glu Met Glu Thr Asn Ile Met Gly 65 70 75 80 Cys Tyr TrpPro Asn Pro Leu Ala Gln Ser Phe Ile Thr Gly Ile His 85 90 95 Arg Gln PhePhe Ser Asn Cys Thr Val Asp Arg Thr His Trp Glu Asp 100 105 110 Pro ProAsp Glu Val Leu Ile Pro Leu Ile Ala Val Pro Val Val Leu 115 120 125 ThrVal Ala Met Ala Gly Leu Val Val Trp Arg Ser Lys His Thr Asp 130 135 140Arg Leu Leu 145 65 634 DNA Rattus norvegicus CDS (12)..(455) 65cttagctggc c atg gcg acc ccg gca cag cgg ctg cac ctt ctc cct ctg 50 MetAla Thr Pro Ala Gln Arg Leu His Leu Leu Pro Leu 1 5 10 ttg ctg ctg ctttgt ggt gag tgt gcc caa gta tgc ggt tgc aat gag 98 Leu Leu Leu Leu CysGly Glu Cys Ala Gln Val Cys Gly Cys Asn Glu 15 20 25 aca gga atg ctg gagagg ttg cct cgc tgt ggg aaa gcc ttt gcc gaa 146 Thr Gly Met Leu Glu ArgLeu Pro Arg Cys Gly Lys Ala Phe Ala Glu 30 35 40 45 atg atg cag aag gtggac gtc tgg aag tgg tgc aac ctg tcg gag ttc 194 Met Met Gln Lys Val AspVal Trp Lys Trp Cys Asn Leu Ser Glu Phe 50 55 60 atc gtg tac tac gaa agcttc act aac tgc acg gag atg gag aca aac 242 Ile Val Tyr Tyr Glu Ser PheThr Asn Cys Thr Glu Met Glu Thr Asn 65 70 75 atc gtg ggc tgc tac tgg cccaac ccg ctg gcc cag agc ttt atc acg 290 Ile Val Gly Cys Tyr Trp Pro AsnPro Leu Ala Gln Ser Phe Ile Thr 80 85 90 ggt atc cat agg cag ttc ttt tccaac tgc act gtg gac agg acc cac 338 Gly Ile His Arg Gln Phe Phe Ser AsnCys Thr Val Asp Arg Thr His 95 100 105 tgg gaa gac ccc ccg gat gaa gttctc atc cca ctt atc gca gtt cca 386 Trp Glu Asp Pro Pro Asp Glu Val LeuIle Pro Leu Ile Ala Val Pro 110 115 120 125 gtc ttg ctg acc gtg gct atggct ggc ctg gtg gtg tgg cgt agc aag 434 Val Leu Leu Thr Val Ala Met AlaGly Leu Val Val Trp Arg Ser Lys 130 135 140 cac act gac cgg ctt ctg tgagggcctgcgg gatggaaggc cgtgcctggc 485 His Thr Asp Arg Leu Leu 145aagctagaag aatgtcgccc agagctctga gagcctgcag actctgtttc tgtctggtct 545gccttggcca caccctacct ggtcgtgtca aagtcctcct gactagactg acgtggccct 605tgctgtctag cctgctgcct ggtggggtt 634 66 147 PRT Rattus norvegicus 66 MetAla Thr Pro Ala Gln Arg Leu His Leu Leu Pro Leu Leu Leu Leu 1 5 10 15Leu Cys Gly Glu Cys Ala Gln Val Cys Gly Cys Asn Glu Thr Gly Met 20 25 30Leu Glu Arg Leu Pro Arg Cys Gly Lys Ala Phe Ala Glu Met Met Gln 35 40 45Lys Val Asp Val Trp Lys Trp Cys Asn Leu Ser Glu Phe Ile Val Tyr 50 55 60Tyr Glu Ser Phe Thr Asn Cys Thr Glu Met Glu Thr Asn Ile Val Gly 65 70 7580 Cys Tyr Trp Pro Asn Pro Leu Ala Gln Ser Phe Ile Thr Gly Ile His 85 9095 Arg Gln Phe Phe Ser Asn Cys Thr Val Asp Arg Thr His Trp Glu Asp 100105 110 Pro Pro Asp Glu Val Leu Ile Pro Leu Ile Ala Val Pro Val Leu Leu115 120 125 Thr Val Ala Met Ala Gly Leu Val Val Trp Arg Ser Lys His ThrAsp 130 135 140 Arg Leu Leu 145 67 1218 DNA Rattus norvegicus CDS(31)..(474) 67 tgctgtaagc cgagtgcatc ttagctggcc atg gcg acc cca gca cagcgg ctg 54 Met Ala Thr Pro Ala Gln Arg Leu 1 5 cac ctt ctc cct ctg ttgctg ctg ctt tgt ggt gag tgt gcc caa gta 102 His Leu Leu Pro Leu Leu LeuLeu Leu Cys Gly Glu Cys Ala Gln Val 10 15 20 tgc ggt tgc aat gag aca ggaatg ctg gag agg ttg cct cgc tgt ggg 150 Cys Gly Cys Asn Glu Thr Gly MetLeu Glu Arg Leu Pro Arg Cys Gly 25 30 35 40 aaa gcc ttt gcc gaa atg atgcag aag gtg gac gtc tgg aag tgg tgc 198 Lys Ala Phe Ala Glu Met Met GlnLys Val Asp Val Trp Lys Trp Cys 45 50 55 aac ctg tcg gag ttc atc gtg tactac gaa agc ttc act aac tgc acg 246 Asn Leu Ser Glu Phe Ile Val Tyr TyrGlu Ser Phe Thr Asn Cys Thr 60 65 70 gag atg gag aca aac atc gtg ggc tgctac tgg ccc aac ccg ctg gcc 294 Glu Met Glu Thr Asn Ile Val Gly Cys TyrTrp Pro Asn Pro Leu Ala 75 80 85 cag agc ttt atc acg ggt atc cat agg cagttc ttt tcc aac tgc act 342 Gln Ser Phe Ile Thr Gly Ile His Arg Gln PhePhe Ser Asn Cys Thr 90 95 100 gtg gac agg acc cac tgg gaa gac ccc ccggat gaa gtt ctc atc cca 390 Val Asp Arg Thr His Trp Glu Asp Pro Pro AspGlu Val Leu Ile Pro 105 110 115 120 ctt atc gca gtt cca gtc ttg ttg accgtg gct atg gct ggg ctg gtg 438 Leu Ile Ala Val Pro Val Leu Leu Thr ValAla Met Ala Gly Leu Val 125 130 135 gta tgg cgt agc aag cgc act gac cggctt ctg tga gggcctgcgg 484 Val Trp Arg Ser Lys Arg Thr Asp Arg Leu Leu140 145 gatggaaggc cgtgcctggc aagctagaag aatgtcgccc agagctctgagagcctgcag 544 actctgtttc tgtctggtct gccttggcca caccctacct ggtcgtgtcaaagtcctcct 604 gactagactg acgtggccct tgctgtctag cctgctgcct ggtggggttcaggctgcccc 664 gacaggtgct tcactctttc ttgggctagt ggaagaaagt gacaaacctcacatttgtgt 724 accaggcgtg gaaatcatct cttgctgagt cccaccctcc ctgggctgaattcccgagtt 784 tctagacatt tcttggcaga gtctggccca gcctcaaccc taacccaggtcctgacccat 844 ttctatccct gaccctgacc tctgctacgc ttggggcaga gagggcaggcaaggtcatct 904 ggaaggtgtg gcgtcccgag cagaaagaga gatgagcaca ttctctgttggacatgaagg 964 gtagtcgggg ggattgggga atggagttgt taggagtcat gtgtgacctacggacctgcc 1024 tgtcttctag gcgatctgcc atgattctgt gtccagtgtg ggctggagctgtgatttgtt 1084 taacccttca gacacctacc ctgaagatag agagtgaacc tccttcctgaggggtattcc 1144 tgggggtgag gcacgctctg agcgtgctca agggttctgt ctgctgatgtctgctttctg 1204 attaaagtgt ctcc 1218 68 147 PRT Rattus norvegicus 68 MetAla Thr Pro Ala Gln Arg Leu His Leu Leu Pro Leu Leu Leu Leu 1 5 10 15Leu Cys Gly Glu Cys Ala Gln Val Cys Gly Cys Asn Glu Thr Gly Met 20 25 30Leu Glu Arg Leu Pro Arg Cys Gly Lys Ala Phe Ala Glu Met Met Gln 35 40 45Lys Val Asp Val Trp Lys Trp Cys Asn Leu Ser Glu Phe Ile Val Tyr 50 55 60Tyr Glu Ser Phe Thr Asn Cys Thr Glu Met Glu Thr Asn Ile Val Gly 65 70 7580 Cys Tyr Trp Pro Asn Pro Leu Ala Gln Ser Phe Ile Thr Gly Ile His 85 9095 Arg Gln Phe Phe Ser Asn Cys Thr Val Asp Arg Thr His Trp Glu Asp 100105 110 Pro Pro Asp Glu Val Leu Ile Pro Leu Ile Ala Val Pro Val Leu Leu115 120 125 Thr Val Ala Met Ala Gly Leu Val Val Trp Arg Ser Lys Arg ThrAsp 130 135 140 Arg Leu Leu 145 69 1234 DNA Rattus norvegicus CDS(33)..(476) 69 gttgctgtaa gccgagtgca tcttagctgg cc atg gcg acc ccg gcacag cgg 53 Met Ala Thr Pro Ala Gln Arg 1 5 ctg cac ctt ctc cct ctg ttgctg ctg ctt tgt ggt gag tgt gcc caa 101 Leu His Leu Leu Pro Leu Leu LeuLeu Leu Cys Gly Glu Cys Ala Gln 10 15 20 gta tgc ggt tgc aat gag aca ggaatg ctg gag agg ttg cct cgc tgt 149 Val Cys Gly Cys Asn Glu Thr Gly MetLeu Glu Arg Leu Pro Arg Cys 25 30 35 ggg aaa gcc ttt gcc gaa atg atg cagaag gtg gac gtc tgg aag tgg 197 Gly Lys Ala Phe Ala Glu Met Met Gln LysVal Asp Val Trp Lys Trp 40 45 50 55 tgc aac ctg tcg gag ttc atc gtg tactac gaa agc ttc act aac tgc 245 Cys Asn Leu Ser Glu Phe Ile Val Tyr TyrGlu Ser Phe Thr Asn Cys 60 65 70 acg gag atg gag aca aac atc gtg ggc tgctac tgg ccc aac ccg ctg 293 Thr Glu Met Glu Thr Asn Ile Val Gly Cys TyrTrp Pro Asn Pro Leu 75 80 85 gcc cag agc ttt atc acg ggt atc cat agg cagttc ttt tcc aac tgc 341 Ala Gln Ser Phe Ile Thr Gly Ile His Arg Gln PhePhe Ser Asn Cys 90 95 100 act gtg gac agg acc cac tgg gaa gac ccc ccggat gaa gtt ctc atc 389 Thr Val Asp Arg Thr His Trp Glu Asp Pro Pro AspGlu Val Leu Ile 105 110 115 cca ctt atc gca gtt cca gtc ttg ttg acc gtggct atg gct ggg ctg 437 Pro Leu Ile Ala Val Pro Val Leu Leu Thr Val AlaMet Ala Gly Leu 120 125 130 135 gtg gta tgg cgt agc aag cgc act gac cggctt ctg tga gggcctgcgg 486 Val Val Trp Arg Ser Lys Arg Thr Asp Arg LeuLeu 140 145 gatggaaggc cgtgcctggc aagctagaag aatgtcgccc agagctctgagagcctgcag 546 actctgtttc tgtctggtct gccttggcca caccctacct ggtcgtgtcaaagtcctcct 606 gactagactg acgtggccct tgctgtctag cctgctgcct ggtggggttcaggctgcccc 666 gacaggtgct tcactctttc ttgggctagt ggaagaaagt gacaaacctcacatttgtgt 726 accaggcgtg gaaatcatct cttgctgagt cccaccctcc ctgggctgaattcccgagtc 786 tctagacatt tcttggcaga gtctggccca gcctcaaccc taacccaggtcctgacccat 846 ttctatccct gaccctgacc tctgctacgc ttggggcaga gagggcaggcaaggtcatct 906 ggaaggtgtg gcgtcccgag cagaaagaga gatgagcaca ttctctgttggacatgaaga 966 gtagtcgggg ggattgggga atggagttgt taggagtcat gtgtgacctacggacctgcc 1026 tgtcttctag gcgatctgcc atgattctgt gtccagtgtg ggctggagctgtgatttgtt 1086 taacccttca gatccctacc ctgaagatag agagtgaacc tccttcctgaggggtattcc 1146 tgggggtgag gcacgctctg agcgtgctca agggttctgt ctgctgatgtctgctttctg 1206 attaaagtgt ctccttacaa aaaaaaaa 1234 70 147 PRT Rattusnorvegicus 70 Met Ala Thr Pro Ala Gln Arg Leu His Leu Leu Pro Leu LeuLeu Leu 1 5 10 15 Leu Cys Gly Glu Cys Ala Gln Val Cys Gly Cys Asn GluThr Gly Met 20 25 30 Leu Glu Arg Leu Pro Arg Cys Gly Lys Ala Phe Ala GluMet Met Gln 35 40 45 Lys Val Asp Val Trp Lys Trp Cys Asn Leu Ser Glu PheIle Val Tyr 50 55 60 Tyr Glu Ser Phe Thr Asn Cys Thr Glu Met Glu Thr AsnIle Val Gly 65 70 75 80 Cys Tyr Trp Pro Asn Pro Leu Ala Gln Ser Phe IleThr Gly Ile His 85 90 95 Arg Gln Phe Phe Ser Asn Cys Thr Val Asp Arg ThrHis Trp Glu Asp 100 105 110 Pro Pro Asp Glu Val Leu Ile Pro Leu Ile AlaVal Pro Val Leu Leu 115 120 125 Thr Val Ala Met Ala Gly Leu Val Val TrpArg Ser Lys Arg Thr Asp 130 135 140 Arg Leu Leu 145

What is claimed:
 1. A method for identifying candidate compounds forregulating skeletal muscle mass or function, comprising: a. contacting atest compound with an amylin receptor; b. determining whether the testcompound binds to the amylin receptor; and c. identifying those testcompounds that bind the amylin receptor as candidate compounds forregulating skeletal muscle mass or function.
 2. A method for identifyingcandidate compounds for regulating skeletal muscle mass or functionaccording to claim 1, further comprising: a. selecting those compoundsthat bind amylin receptor and further determining whether the testcompound increases muscle mass or function in a skeletal muscle atrophymodel system; and b. identifying those test compounds that modulatemuscle mass or function as candidate compounds for regulating skeletalmuscle mass or function.
 3. The method for identifying candidatecompounds according to claim 1 wherein, the amylin receptor comprises anamino acid sequence of calcitonin receptor that is 90% homologous to SEQID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34,36, 38, 40, 42, or 44; and an amino acid sequence of either receptoractivity modifying protein 1 (RAMP1) or receptor activity modifyingprotein 3 (RAMP3) that is 90% homologous to SEQ ID NOS: 46, 48, 50, 52,54, 56, 58, 60, 62, 64, 66, 68, or
 70. 4. The method for identifyingcandidate compounds according to claim 1 wherein, the amylin receptorcomprises an amino acid sequence of calcitonin receptor of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38,40, 42, or 44; and an amino acid sequence of either receptor activitymodifying protein 1 (RAMP1) or receptor activity modifying protein 3(RAMP3) of SEQ ID NOS: 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68,or
 70. 5. A method for identifying candidate compounds for regulatingskeletal muscle mass or function, comprising: a. contacting a testcompound with a cell expressing a functional amylin receptor; b.determining whether the test compound activates the amylin receptor; andc. identifying those test compounds which activate the amylin receptoras candidate compounds for regulating skeletal muscle mass or function.6. A method for identifying candidate compounds for regulating skeletalmuscle mass or function according to claim 5, further comprising: c.selecting those compounds that bind amylin receptor and furtherdetermining whether the test compound increases muscle mass or functionin a skeletal muscle atrophy model system; and d. identifying those testcompounds that modulate muscle mass or function as candidate compoundsfor regulating skeletal muscle mass or function.
 7. The method foridentifying candidate compounds according to claim 5 wherein, the amylinreceptor comprises an amino acid sequence of calcitonin receptor that is90% homologous to SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,24, 26, 28, 30, 32, 34, 36, 38, 40, 42, or 44; and a sequence of eitherreceptor activity modifying protein 1 (RAMP1) or receptor activitymodifying protein 3 (RAMP3) that is 90% homologous to SEQ ID NOS: 46,48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, or
 70. 8. The method foridentifying candidate compounds according to claim 5 wherein, the amylinreceptor comprises an amino acid sequence of calcitonin receptor of SEQID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34,36, 38, 40, 42, or 44; and a sequence of either receptor activitymodifying protein 1 (RAMP1) or receptor activity modifying protein 3(RAMP3) of SEQ ID NOS: 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68,or
 70. 9. The method for identifying candidate compounds according toclaim 5 wherein, determining whether the test compound activates amylinreceptor involves measuring cellular cAMP levels.
 10. The method foridentifying candidate compounds according to claim 5, wherein the methodfurther comprises a reporter gene operatively associated with a cAMPresponsive element and measuring the expression of the reporter gene isanalogous to measuring cAMP levels.
 11. A method for identifyingcandidate compounds for regulating skeletal muscle mass or functioncomprising: a. contacting a test compound with a cell expressing afunctional amylin receptor, and determining the level of activation ofthe amylin receptor; b. contacting the test compound with a cellexpressing a functional calcitonin receptor, and determining the levelof activation of the calcitonin receptor; c. comparing the level ofamylin receptor activation in the cell expressing a functional amylinreceptor to the level of calcitonin receptor activation in the cellexpressing calcitonin receptor; and d. identifying those test compoundsthat show selectivity for amylin receptor as candidate compounds forregulating skeletal muscle mass or function.
 12. The method according toclaim 11 wherein the candidate compound exhibits about 100-fold orgreater selectivity for amylin receptor over calcitonin receptor. 13.The method according to claim 11 wherein the candidate compound exhibitsabout 1000-fold or greater selectivity for amylin receptor overcalcitonin receptor.
 14. A method for identifying candidate compoundsfor regulating skeletal muscle mass or function by identifying compoundsthat prolong or augment the agonist-induced activation of an amylinreceptor or of an amylin receptor signal transduction pathway,comprising; a. contacting a test compound with a first cell populationwhich expresses a functional amylin receptor; b. treating a second cellpopulation with an amylin receptor agonist for a sufficient time and ata sufficient concentration to cause desensitization of the amylinreceptor; further treating the second cell population with the testcompound; c. determining the level of activation of the amylin receptorin the first and second cell population; and d. identifying those testcompounds that prolong or augment the activation of an amylin receptoror of an amylin receptor signal transduction pathway as candidatecompounds for regulating skeletal muscle mass or function.
 15. A methodfor identifying candidate therapeutic compounds from a group of one ormore candidate compounds which have been previously determined to bind,or activate an amylin receptor; or prolong, or augment the activation ofan amylin receptor or of an amylin receptor signal transduction pathwaycomprising: a. administering the candidate compound, or the candidatecompound in conjunction with an amylin receptor agonist, to a non-humananimal; and b. determining whether the candidate compound regulatesskeletal muscle mass or function in the treated animal.
 16. A method foridentifying candidate compounds for regulating skeletal muscle mass orfunction by identifying compounds that increase expression of amylin oramylin receptor, comprising: a. contacting a test compound with a cellor cell lysate containing a reporter gene operatively associated withcalcitonin receptor gene regulatory element, receptor activity modifyingprotein gene regulatory element, or an amylin gene regulatory element;b. detecting expression of the reporter gene; and c. identifying thosetest compounds that increase expression of the reporter gene ascandidate compounds for regulating skeletal muscle mass or function. 17.A method for increasing skeletal muscle mass or function in a subject inwhich such an increase is desirable, comprising: a. identifying asubject in which an increase in muscle mass or function is desirable;and b. administering to the subject a safe and effective amount of acompound selected from the group consisting of an amylin receptoragonist, a compound that augments or prolongs amylin receptor or amylinreceptor signal transduction pathway activation, an expression vectorencoding a functional amylin receptor, an expression vector encoding aconstitutively active amylin receptor, an expression vector encodingamylin and a compound that increases expression of an amylin receptor oramylin.
 18. The method of claim 17 for increasing muscle mass orfunction wherein the subject in which such an increase is desirable ischaracterized by presence of muscle atrophy.
 19. The method for treatingskeletal muscle atrophy according to claim 17 wherein the compound is anamylin receptor agonist.
 20. A pharmaceutical composition, comprising:a. a safe and effective amount of an amylin receptor agonist; and b. apharmaceutically-acceptable carrier.
 21. The pharmaceutical compositionaccording to claim 20 wherein the amylin receptor agonist is a chimericor human antibody specific for an amylin receptor.
 22. Thepharmaceutical composition according to claim 20 wherein the amylinreceptor agonist is amylin.